N-aroyl cyclic amines

ABSTRACT

Disclosed are N-aroyl cyclic amine derivatives having the formula: 
     
       
         
         
             
             
         
       
     
     wherein the substituent variables are as defined herein, and their use as pharmaceuticals.

This application is a divisional of application Ser. No. 10/477,008,filed Nov. 5, 2003, which is a 371 of International Application No.PCT/GB02/02042, filed May 2, 2002.

This invention relates to N-aroyl cyclic amine derivatives and their useas pharmaceuticals.

Many medically significant biological processes are mediated by proteinsparticipating in signal transduction pathways that involve G-proteinsand/or second messengers.

Polypeptides and polynucleotides encoding the human 7-transmembraneG-protein coupled neuropeptide receptor, orexin-1 (HFGAN72), have beenidentified and are disclosed in EP-A-875565, EP-A-875566 and WO96/34877. Polypeptides and polynucleotides encoding a second humanorexin receptor, orexin-2 (HFGANP), have been identified and aredisclosed in EP-A-893498.

Polypeptides and polynucleotides encoding polypeptides which are ligandsfor the orexin-1 receptor, e.g. orexin-A (Lig72A) are disclosed inEP-A-849361.

Orexin receptors are found in the mammalian host and may be responsiblefor many biological functions, including pathologies including, but notlimited to, depression; anxiety; addictions; obsessive compulsivedisorder; affective neurosis/disorder; depressive neurosis/disorder;anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder;sexual dysfunction; psychosexual dysfunction; sex disorder; sexualdisorder; schizophrenia; manic depression; delirium; dementia; severemental retardation and dyskinesias such as Huntington's disease andGilles de la Tourett's syndrome; disturbed biological and circadianrhythms; feeding disorders, such as anorexia, bulimia, cachexia, andobesity; diabetes; appetite/taste disorders; vomiting/nausea; asthma;cancer; Parkinson's disease; Cushing's syndrome/disease; basophiladenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysistumor/adenoma; hypothalamic diseases; Froehlich's syndrome;adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma;pituitary growth hormone; adrenohypophysis hypofunction;adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman'ssyndrome (anosmia, hyposmia); functional or psychogenic amenorrhea;hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenaldysfunction; idiopathic hyperprolactinemia; hypothalamic disorders ofgrowth hormone deficiency; idiopathic growth hormone deficiency;dwarfism; gigantism; acromegaly; disturbed biological and circadianrhythms; and sleep disturbances associated with such diseases asneurological disorders, neuropathic pain and restless leg syndrome,heart and lung diseases; acute and congestive heart failure;hypotension; hypertension; urinary retention; osteoporosis; anginapectoris; myocardial infarction; ischaemic or haemorrhagic stroke;subarachnoid haemorrhage; head injury such as sub-arachnoid haemorrhageassociated with traumatic head injury; ulcers; allergies; benignprostatic hypertrophy; chronic renal failure; renal disease; impairedglucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggeratedsensitivity to pain, such as hyperalgesia, causalgia and allodynia;acute pain; bum pain; atypical facial pain; neuropathic pain; back pain;complex regional pain syndromes I and II; arthritic pain; sports injurypain; pain related to infection, e.g. HIV, post-polio syndrome, andpost-herpetic neuralgia; phantom limb pain; labour pain; cancer pain;post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; nausea and vomiting; conditions associated with visceral painincluding irritable bowel syndrome, migraine and angina; urinary bladderincontinence e.g. urge incontinence; tolerance to narcotics orwithdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy;insomnia; parasomnia; jet-lag syndrome; and neurodegenerative disorders,which includes nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration, epilepsy, and seizure disorders.

Experiments have shown that central administration of the ligandorexin-A (described in more detail below) stimulated food intake infreely-feeding rats during a 4 hour time period. This increase wasapproximately four-fold over control rats receiving vehicle. These datasuggest that orexin-A may be an endogenous regulator of appetite.Therefore, antagonists of its receptor may be useful in the treatment ofobesity and diabetes, see Cell, 1998, 92, 573-585.

There is a significant incidence of obesity in westernized societies.According to WHO definitions a mean of 35% of subjects in 39 studieswere overweight and a further 22% clinically obese. It has beenestimated that 5.7% of all healthcare costs in the USA are a consequenceof obesity. About 85% of Type 2 diabetics are obese, and diet andexercise are of value in all diabetics. The incidence of diagnoseddiabetes in westernized countries is typically 5% and there areestimated to be an equal number undiagnosed. The incidence of bothdiseases is rising, demonstrating the inadequacy of current treatmentswhich may be either ineffective or have toxicity risks includingcardiovascular effects. Treatment of diabetes with sulfonylureas orinsulin can cause hypoglycemia, whilst metformin causes GI side-effects.No drug treatment for Type 2 diabetes has been shown to reduce thelong-term complications of the disease. Insulin sensitizers will beuseful for many diabetics, however they do not have an anti-obesityeffect.

Rat sleep/EEG studies have also shown that central administration oforexin-A, an agonist of the orexin receptors, causes a dose-relatedincrease in arousal, largely at the expense of a reduction inparadoxical sleep and slow wave sleep 2, when administered at the onsetof the normal sleep period. Therefore antagonists of its receptor may beuseful in the treatment of sleep disorders including insomnia.

The present invention provides N-aroyl cyclic amine derivatives whichare non-peptide antagonists of human orexin receptors, in particularorexin-1 receptors. In particular, these compounds are of potential usein the treatment of obesity, including obesity observed in Type 2(non-insulin-dependent) diabetes patients, and/or sleep disorders.Additionally these compounds are useful in the treatment of stroke,particularly ischemic or haemorrhagic stroke, and/or blocking the emeticresponse, i.e. useful in the treatment of nausea and vomiting.

International Patent Applications WO99/09024, WO99/58533, WO00/47577 andWO00/47580 disclose phenyl urea derivatives and WO00/47576 disclosesquinolinyl cinnamide derivatives as orexin receptor antagonists.WO01/96302 discloses N-aroyl cyclic amine derivatives.

According to the invention there is provided a compound of formula (I):

wherein:

Y represents a bond, oxygen, or a group (CH₂)_(n), wherein n represents1, 2 or 3

m represents 1, 2, or 3;

p represents 0 or 1;

X is NR, wherein R is H or (C₁₋₄)alkyl;

Ar¹ is aryl, or a mono or bicyclic heteroaryl group containing up to 3heteroatoms selected from N, O and S; any of which may be optionallysubstituted;

Ar² represents phenyl or a 5- or 6-membered heterocyclyl groupcontaining up to 3 heteroatoms selected from N, O and S, wherein thephenyl or heterocyclyl group is substituted by R¹ and further optionalsubstituents; or Ar² represents an optionally substituted bicyclicaromatic or bicyclic heteroaromatic group containing up to 3 heteroatomsselected from N, O and S;

R¹ represents hydrogen, optionally substituted (C₁₋₄)alkoxy, halo,cyano, optionally substituted (C₁₋₆)alkyl, optionally substitutedphenyl, or an optionally substituted 5- or 6-membered heterocyclyl groupcontaining up to 4 heteroatoms selected from N, O and S;

wherein when Y is a bond Ar² can not be 2-naphthyl;

when Ar¹ is aryl p is not 1;

or a pharmaceutically acceptable salt thereof.

X is preferably NH.

m is preferably 1.

p is preferably 0.

Even more preferably m is 1 when p is 0.

Preferably R is hydrogen.

Alternatively compounds of formula (I) are compounds of formula (Ia);

wherein:

Y represents a bond, oxygen, or a group (CH₂)_(n), wherein n represents1, 2 or 3

Ar¹ is a mono or bicyclic heteroaryl group containing up to 3heteroatoms selected from N, O and S; any of which may be optionallysubstituted;

Ar² represents phenyl or a 5- or 6-membered heterocyclyl groupcontaining up to 3 heteroatoms selected from N, O and S, wherein thephenyl or heterocyclyl group is substituted by R¹ and further optionalsubstituents; or Ar² represents an optionally substituted bicyclicaromatic or bicyclic heteroaromatic group containing up to 3 heteroatomsselected from N, O and S;

R¹ represents hydrogen, optionally substituted (C₁₋₄)alkoxy, halo,cyano, optionally substituted (C₁₋₆)alkyl, optionally substitutedphenyl, or an optionally substituted 5- or 6-membered heterocyclyl groupcontaining up to 4 heteroatoms selected from N, O and S;

wherein when Y is a bond then Ar² can not be 2-naphthyl;

or pharmaceutically acceptable salts thereof.

Preferably where Ar² represents phenyl or a 5- or 6-memberedheterocyclyl group containing up to 3 heteroatoms selected from N, O andS, the R¹ group is situated adjacent to the point of attachment to theamide carbonyl.

Y is preferably a bond, oxygen or (CH₂)_(n) wherein n is 1 or 2.

Even more preferably Y is a bond, oxygen or (CH₂)_(n) wherein n is 1

Alternatively R¹ represents hydrogen, optionally substituted(C₁₋₄)alkoxy, halo, optionally substituted (C₁₋₆)alkyl, optionallysubstituted phenyl or an optionally substituted 5- or 6-memberedheterocyclyl group containing up to 3 heteroatoms selected from N, O andS.

Alternatively R¹ represents optionally substituted (C₁₋₄)alkoxy, halo,optionally substituted (C₁₋₆)alkyl, optionally substituted phenyl or anoptionally substituted 5- or 6-membered heterocyclyl group containing upto 3 heteroatoms selected from N, O and S.

Preferably R¹ is selected from trifluoromethoxy, methoxy, ethoxy, halo,cyano or an optionally substituted phenyl, pyridyl, pyrazolyl,pyrimidinyl, or oxadiazolyl group.

More preferably R¹ is selected from trifluoromethoxy, methoxy, ethoxy,halo, or an optionally substituted phenyl, pyridyl, pyrazolyl,pyrimidinyl, or oxadiazolyl group.

When Ar¹ is optionally substituted aryl it is preferably phenyl. Ar¹ mayhave up to 5, preferably 1, 2 or 3 optional substituents.

Examples of when Ar¹ is a mono or bicyclic heteroaryl are quinoxalinyl,quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl,benzimidazolyl, naphthyridinyl, pyridinyl, pyrimidinyl, or thiazolyl.Additionally Ar¹ can be selected from pyridazinyl, pyrazinyl, oxazolyl,triazolyl, imidazolyl, pyrazolyl, quinolinyl, benzofuranyl, indolyl,benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl orisoquinolinyl. Furthermore Ar¹ can be furanyl or thienyl.

Preferably Ar¹ is benzoxazolyl, benzimidazolyl, quinoxalinyl,quinazolinyl, pyrimidinyl, pyridinyl, naphthyridinyl, Additionally Ar¹can be quinolinyl, pyridopyrimidine, thiazolyl, oxazolylpyridinyl,benzothiazolyl, isoquinolinyl or pyrazinyl.

More preferably Ar¹ is benzoxazolyl, benzimidazolyl, quinoxalinyl,quinazolinyl, pyrimidinyl, pyridinyl, naphthyridinyl oroxazolyl[4,5-b]pyridinyl.

When Ar² is a 5- or 6-membered heterocyclyl group containing up to 3heteroatoms selected from N, O and S, it may be furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl,isoxazolyl, pyrazinyl or pyrazolyl.

When R¹ is a 5- or 6-membered heterocyclyl group containing up to 4heteroatoms selected from N, O and S, it may be furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl,isoxazolyl, pyrazinyl or pyrazolyl. Additionally it can be tetrazoyl,piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl.

Preferably when R¹ is a 5- or 6-membered heterocyclic ring containing upto 4 heteroatoms selected from N, O and S, it is furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl,isoxazolyl, pyrazinyl or pyrazolyl.

Preferably R¹ is a 5- or 6-membered heterocyclic ring it contains up to3 heteroatoms selected from N, O and S.

When Ar² is an optionally substituted bicyclic aromatic or bicyclicheteroaromatic it is selected from benzofuryl, benzimidazolyl,quinolinyl, quinoxalinyl or naphthyl. Additionally it may bebenzotriazolyl, benzothienyl, benzoxazolyl, naphthyridinyl,isoquinolinyl or quinazolinyl. Furthermore it can be indolyl,benzothiazolyl, or benzothiadiazolyl.

Preferably Ar² represents optionally substituted phenyl, pyridyl,thiazolyl, pyrazolyl, benzofuryl, naphthyl, triazolyl, quinoxalinyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl, benzotriazolyl,benzothiazolyl, indolyl or thienyl.

Alternatively Ar² represents optionally substituted phenyl, pyridyl,thiazolyl, pyrazolyl, benzofuryl, naphthyl or triazolyl. Preferably thetriazolyl is 1,2,3-triazolyl.

More preferably Ar² represents optionally substituted thiazolyl,pyrazolyl or quinolinyl.

Alternatively R¹ is selected from trifluoromethoxy, methoxy, halo, or anoptionally substituted phenyl, pyridyl, pyrazolyl or oxadiazolyl group

Even more preferably R¹ represents a trifluoromethoxy group, methoxygroup, iodo, or an optionally substituted phenyl, pyridyl, oroxadiazolyl group.

Optional substituents for the groups Ar¹, Ar², R and R¹ include halogen,hydroxy, oxo, cyano, nitro, (C₁₋₄)alkyl, (C₁₋₄)alkoxy,hydroxy(C₁₋₄)alkyl, hydroxy(C₁₋₄)alkoxy, halo(C₁₋₄)alkyl,halo(C₁₋₄)alkoxy, aryl(C₁₋₄)alkoxy, (C₁₋₄)alkylthio, hydroxy(C₁₋₄)alkyl,(C₁₋₄)alkoxy(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl(C₁₋₄)alkoxy, (C₁₋₄)alkanoyl,(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylsulfonyl, (C₁₋₄)alkylsulfonyloxy,(C₁₋₄)alkylsulfonyl(C₁₋₄)alkyl, arylsulfonyl, arylsulfonyloxy,arylsulfonyl(C₁₋₄)alkyl, (C₁₋₄)alkylsulfonamido, (C₁₋₄)alkylamido,(C₁₋₄)alkylsulfonamido(C₁₋₄)alkyl, (C₁₋₄)alkylamido(C₁₋₄)alkyl,arylsulfonamido, arylcarboxamido, arylsulfonamido(C₁₋₄)alkyl,arylcarboxamido(C₁₋₄)alkyl, aroyl, aroyl(C₁₋₄)alkyl, oraryl(C₁₋₄)alkanoyl group; a group R^(a)R^(b)N—, R^(a)OCO(CH₂)_(r),R^(a)CON(R^(a))(CH₂)_(r), R^(a)R^(b)NCO(CH₂)_(r),R^(a)R^(b)NSO₂(CH₂)_(r) or R^(a)SO₂NR^(b)(CH₂)_(r) where each of R^(a)and R^(b) independently represents a hydrogen atom or a (C₁₋₄)alkylgroup or where appropriate R^(a)R^(b) forms part of a(C₃₋₆)azacyloalkane or (C₃₋₆)(2-oxo)azacycloalkane ring and r representszero or an integer from 1 to 4. Additional substituents are (C₁₋₄)acyl,aryl, aryl(C₁₋₄)alkyl, (C₁₋₄)alkylamino(C₁₋₄)alkyl, R^(a)R^(b)N(CH₂)n-,R^(a)R^(h)N(CH₂)nO-, wherein n represents an integer from 1 to 4.Additionally when the substituent is R^(a)R^(b)N(CH₂)n- orR^(a)R^(b)N(CH₂)nO, R^(a) with at least one CH₂ of the (CH₂)n portion ofthe group form a (C₃₋₆)azacycloalkane and R^(b) represents hydrogen, a(C₁₋₄)alkyl group or with the nitrogen to which it is attached forms asecond (C₃₋₆)azacycloalkane fused to the first (C₃₋₆)azacycloalkane.

Preferred optional substituents for Ar² are halogen, cyano, (C₁₋₄)alkyl.Additional preferred optional substituents are hydroxy(C₁₋₄)alkyl,(C₁₋₄)alkoxy(C₁₋₄)alkyl, R^(a)R^(b)N(CH₂)n, R^(a)R^(b)N. Furtheroptional substituents for Ar² can also be halogen, cyano, (C₁₋₄)alkyl,R^(a)R^(b)N(CH₂)nO or (C₁₋₄)alkoxy.

Preferred optional substituents for Ar¹ are halogen, cyano,(C₁₋₄)alkanoyl. Other preferred substituents are hydroxy(C₁₋₄)alkyl,(C₁₋₄)alkyl or CF₃.

Preferred optional substituents for R¹ are halogen,(C₁₋₄)alkoxy(C₁₋₄)alkyl, R^(a)R^(b)N, R^(a)R^(b)N(CH₂)nO andR^(a)R^(b)N(CH₂)n. Other preferred substituents are (C₁₋₄)alkoxy or(C₁₋₄)alkanoyl.

In the groups Ar¹ and Ar², substituents positioned ortho to one anothermay be linked to form a ring.

Illustrative compounds of formula (I) are selected from:

Example Compound Name 11-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-methyl-5-phenyl-thiazol-4-yl)-methanone. 21-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-biphenyl-2-yl-methanone 31-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 41-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)-methanone 51-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-naphthalen-1-yl-methanone 61-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-methoxy-phenyl)-methanone 71-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-iodo-phenyl)-methanone 81-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)-methanone 91-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 101-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-biphenyl-2-yl-methanone 111-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-iodo-phenyl)-methanone 121-[2-Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-phenyl-methanone 131-{2-[(1H-Benzoimidazol-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 141-{2-[(1H-Benzoimidazol-2-ylamino)-methyl]-piperidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 151-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 161-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)-methanone 171-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-biphenyl-2-yl-methanone 181-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-methyl-5-phenyl-thiazol-4-yl)-methanone 191-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(isoquinolin-1-ylaminomethyl)-piperidin-1-yl]-methanone 201-[2-(Isoquinolin-1-ylaminomethyl)-piperidin-1-yl]-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 211-[2-(Isoquinolin-1-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)-methanone 221-(2-Iodo-phenyl)-1-[2-(isoquinolin-1-ylaminomethyl)-piperidin-1-yl]-methanone 231-[2-(Isoquinolin-1-ylaminomethyl)-piperidin-1-yl]-1-naphthalen-1-yl-methanone 241-[2-(Quinoxalin-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)-methanone 251-[2-(Quinoxalin-2-ylaminomethyl)-piperidin-1-yl]-1-(3-trifluoromethoxy-phenyl)-methanone 261-(2-Iodo-phenyl)-1-[2-(quinoxalin-2-ylaminomethyl)-piperidin-1-yl]-methanone 271-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(quinoxalin-2-ylaminomethyl)-piperidin-1-yl]-methanone 281-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[2-(quinoxalin-2-ylaminomethyl)-piperidin-1-yl]-methanone 291-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(R)-2-(quinazolin-2-ylaminomethyl)-piperidin-1-yl]-methanone 301-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-([1,5]naphthyridin-2-ylaminomethyl)-piperidin-1-yl]-methanone 311-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-([1,8]naphthyridin-2-ylaminomethyl)-piperidin-1-yl]-methanone 321-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 331-[3-(Benzooxazol-2-ylaminomethyl)-morpholin-4-yl]-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 341-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(quinolin-2-ylaminomethyl)-piperidin-1-yl]-methanone 351-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[2-(quinolin-2-ylaminomethyl)-piperidin-1-yl]-methanone 361-[2-(Quinolin-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)-methanone 371-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-naphthalen-1-yl-methanone 381-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-(quinolin-2-ylaminomethyl)-piperidin-1-yl]-methanone 391-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(pyrimidin-2-ylaminomethyl)-piperidin-1-yl]-methanone 401-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[2-(pyrimidin-2-ylaminomethyl)-piperidin-1-yl]-methanone 411-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(pyrazin-2-ylaminomethyl)-piperidin-1-yl]-methanone 421-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-(quinazolin-4-ylaminomethyl)-piperidin-1-yl]-methanone 431-[5-(4-Fluoro-phenyl)-thiazol-4-yl]-1-[(S)-2-(quinazolin-4-ylaminomethyl)-piperidin-1-yl]-methanone 441-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-1-[(S)-2-(quinazolin-4-ylaminomethyl)-piperidin-1-yl]-methanone 451-[4-(4-Fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl]-1-[(S)-2-(quinazolin-4-ylaminomethyl)-piperidin-1-yl]-methanone 461-[4-(4-Fluoro-phenyl)-1H-pyrazol-3-yl]-1-[(S)-2-(quinazolin-4-ylaminomethyl)-piperidin-1-yl]-methanone 471-[5-(3-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-(quinazolin-4-ylaminomethyl)-piperidin-1-yl]-methanone 481-[5-(3-Fluoro-phenyl)-2-methyl-2H-[1,2,3]triazol-4-yl]-1-[(S)-2-(quinazolin-4-ylaminomethyl)-piperidin-1-yl]-methanone 491-Naphthalen-1-yl-1-[(S)-2-(quinazolin-4-ylaminomethyl)-piperidin-1-yl]-methanone 501-(5-Bromo-2-methoxy-phenyl)-1-[(S)-2-(quinazolin-4-ylaminomethyl)-piperidin-1-yl]-methanone 511-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[(S)-2-(quinazolin-4-ylaminomethyl)-piperidin-1-yl]-methanone 521-[(S)-2-(Quinazolin-4-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)-methanone 531-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 541-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 551-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 561-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 571-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[2-(4-fluoro-phenyl)-5-methyl-2H-pyrazol-3-yl]-methanone 581-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanone 591-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-naphthalen-1-yl-methanone 601-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-quinolin-4-yl-methanone 611-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-oxazol-4-yl]-methanone 621-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 631-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 641-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2-trifluoromethoxy-phenyl)-methanone 651-Biphenyl-2-yl-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanone 661-(5-Bromo-2-methoxy-phenyl)-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanone 671-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 681-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanone 691-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-2H-[1,2,3]triazol-4-yl]-methanone 701-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-naphthalen-1-yl-methanone 711-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 721-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-1-[(R)-2-(quinazolin-2-ylaminomethyl)-piperidin-1-yl]-methanone 731-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[2-(oxazolo[4,5-b]pyridin-2-ylaminomethyl)-piperidin-1-yl]-methanone 741-[2-(Oxazolo[4,5-b]pyridin-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)-methanone 751-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[2-(oxazolo[4,5-b]pyridin-2-ylaminomethyl)-piperidin-1-yl]-methanone 761-(2-Iodo-phenyl)-1-[2-(oxazolo[4,5-b]pyridin-2-ylaminomethyl)-piperidin-1-yl]-methanone 771-{3-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-morpholin-4-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 781-{3-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-morpholin-4-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 791-{3-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-morpholin-4-yl}-1-[4-(4-fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanone 801-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-(pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidin-1-yl]-methanone 811-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-[(S)-2-(pyrido[2,3-b]pyrazin-3-ylaminomethyl)-piperidin-1-yl]-methanone 821-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{2-[(4-phenyl-thiazol-2-ylamino)-methyl]-piperidin-1-yl}-methanone 931-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-methanone 941-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 951-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(4-fluoro-phenyl)-5-methyl-2H-pyrazol-3-yl]-methanone 961-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-2H-[1,2,3]triazol-4-yl]-methanone 972-(1-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanoyl)-benzonitrile 981-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-naphthalen-1-yl-methanone 991-(5-Bromo-2-methoxy-phenyl)-1-{2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 1001-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 1011-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 1021-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 1031-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 1041-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 1051-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[(S)-2-(oxazolo[4,5-b]pyridin-2-ylaminomethyl)-piperidin-1-yl]-methanone 1061-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-{(S)-2-[(methyl-oxazolo[4,5-b]pyridin-2-yl-amino)-methyl]-piperidin-1-yl}-methanone 831-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-quinoxalin-2-yl-methanone 841-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-quinolin-3-yl-methanone 851-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-isoquinolin-3-yl-methanone 861-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2-methoxy-pyridin-3-yl)-methanone 871-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-quinoxalin-6-yl-methanone 886-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-nicotinonitrile 891-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(4-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-methanone 901-(1H-Benzoimidazol-5-yl)-1-[(S)-2-(pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidin-1-yl]-methanone Duplicate of Example 161 911-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[2-dimethylamino-5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 921-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[2-(3-dimethylamino-propoxy)-phenyl]-methanone 1076-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-methyl-amino]-nicotinonitrile 1081-((S)-2-{[(6,7-Difluoro-quinoxalin-2-yl)-methyl-amino]-methyl}-piperidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoneand pharmaceutically acceptable salts thereof.

Additional compounds of formula (I) are selected from:

Example Compund Name 1091-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(4-fluoro-benzofuran-2-yl)-methanone 1102-[((S)-1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-nicotinonitrile 1112-[((S)-1-{1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanoyl}-piperidin-2-ylmethyl)-amino]-nicotinonitrile 1122-[((S)-1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-isonicotinonitrile 1131-Benzo[b]thiophen-2-yl-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanone 1141-(1H-Benzoimidazol-5-yl)-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanone 1151-(1H-Benzotriazol-5-yl)-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanone 1161-Benzothiazol-6-yl-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanone 1171-(3,4-Dichloro-phenyl)-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanone 1181-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(3,4-dimethoxy-phenyl)-methanone 1211-Isoquinolin-3-yl-1-[(S)-2-(pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidin-1-yl]-methanone 1221-(1H-Indol-5-yl)-1-[(S)-2-(pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidin-1-yl]-methanone 1231-[(S)-2-(Pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidin-1-yl]-1-quinolin-4-yl-methanone 1241-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-methanone 1251-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2,4-dimethyl-thiazol-5-yl)-methanone 1261-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-1-methyl-1H-[1,2,3]triazol-4-yl]-methanone 1276-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-nicotinonitrile 1281-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 1291-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 1301-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2H-[1,2,3]triazol-4-yl]-methanone 1311-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-quinolin-2-yl-methanone 1321-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-1-methyl-1H-[1,2,3]triazol-4-yl]-methanone 1331-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone 1341-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 1351-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-quinolin-8-yl-methanone 1362-{[(S)-1-(1-1H-Benzoimidazol-5-yl-methanoyl)-piperidin-2-ylmethyl]-amino}-6,7-difluoro-quinoline-3-carbonitrile 1376,7-Difluoro-2-{[(S)-1-(1-isoquinolin-3-yl-methanoyl)-piperidin-2-ylmethyl]-amino}-quinoline-3-carbonitrile 1386,7-Difluoro-2-[((S)-1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-quinoline-3-carbonitrile 1396,7-Difluoro-2-{[(S)-1-(1-naphthalen-2-yl-methanoyl)-piperidin-2-ylmethyl]-amino}-quinoline-3-carbonitrile 1406,7-Difluoro-2-[((S)-1-{1-[4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-quinoline-3-carbonitrile 1416,7-Difluoro-2-{[(S)-1-(1-1H-indol-6-yl-methanoyl)-piperidin-2-ylmethyl]-amino}-quinoline-3-carbonitrile 1422-{[(S)-1-(1-Benzothiazol-6-yl-methanoyl)-piperidin-2-ylmethyl]-amino}-6,7-difluoro-quinoline-3-carbonitrile 1431-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-naphthalen-2-yl-methanone 1441-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(6-fluoro-benzofuran-2-yl)-methanone 1451-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(5-fluoro-benzofuran-2-yl)-methanone 1461-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(7-fluoro-benzofuran-2-yl)-methanone 1471-(5,7-Difluoro-benzofuran-2-yl)-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanone 1482-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-nicotinonitrile 1492-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-nicotinonitrile 1502-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-isonicotinonitrile 1511-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-{2-[3-(3-dimethylamino-propoxy)-phenyl]-thiophen-3-yl}-methanone 1521-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-{2-[3-(3-dimethylamino-propoxy)-phenyl]-thiophen-3-yl}-methanone 1531-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-quinolin-8-yl-methanone 1541-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(1-methyl-1H-indol-2-yl)-methanone 1551-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-(1H-indol-6-yl)-methanone 1561-Benzo[1,2,3]thiadiazol-5-yl-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanone 1573-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanoyl)-benzoic acid methyl ester 1581-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 1591-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 1601-[4-(4-Fluoro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-1-[(S)-2-(pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidin-1-yl]-methanone 1621-(1H-Benzoimidazol-5-yl)-1-{(S)-2-[(5-bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-methanone 1631-Benzofuran-2-yl-1-{(S)-2-[(5-bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-methanone 1641-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2-methoxy-phenyl)-methanone 1651-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-quinolin-4-yl-methanone 1661-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-1-[3-(3-dimethylamino-propoxy)-phenyl]-methanone 1701-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 1191-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[1-ethyl-4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 1201-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2H-[1,2,3]triazol-4-yl]-methanone 1671-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 1681-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(2-fluoro-phenyl)-thiazol-4-yl]-methanone 1691-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 1711-{2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone 1721-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-1-((S)-2-{[5-(1-hydroxy-ethyl)-pyrimidin-2-ylamino]-methyl}-piperidin-1-yl)-methanone 1732-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile 1743-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanoyl)-N-methyl-benzamideand pharmaceutically acceptable salts thereof.

Further compounds of formula (I) are selected from:

Example Compound Name 1751-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-phenyl-methanone 1761-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone 1771-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 1781-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-quinolin-8-yl-methanone 1791-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-ethoxy-phenyl)-methanone 1801-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-methyl-5-phenyl-thiazol-4-yl)-methanone 1811-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-{5-[3-(3-dimethylamino-propoxy)-phenyl]-2-methyl-thiazol-4-yl}-methanone 1821-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-propoxy-phenyl)-methanone 1831-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-isopropoxy-phenyl)-methanone 1841-(2-Benzyloxy-phenyl)-1-{(S)-2-[(5-bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 1851-[3-(1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanoyl)-4-ethoxy-phenyl]-ethanone 1861-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-ethoxy-6-methoxy-phenyl)-methanone 1871-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-ethoxy-6-methyl-phenyl)-methanone 1881-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-ethoxy-naphthalen-1-yl)-methanone 1891-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 1901-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 1911-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(2-fluoro-phenyl)-thiazol-4-yl]-methanone 1921-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(5-phenyl-thiazol-4-yl)-methanone 1931-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-methyl-4-phenyl-thiazol-5-yl)-methanone 1941-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 1951-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 1961-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone 1971-{(S)-2-[(5-Bromo-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 1981-{(S)-2-[(5-Bromo-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 1991-[3-(Benzooxazol-2-ylaminomethyl)-morpholin-4-yl]-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 2001-{3-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-morpholin-4-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 2011-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(3-fluoro-phenyl)-thiazol-4-yl]-methanone 2021-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-methoxy-phenyl)-2-methyl-thiazol-4-yl]-methanone 2033,5-Difluoro-4-[((S)-1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-benzonitrile 2043,5-Difluoro-4-[((S)-1-{1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-benzonitrile 2053,5-Difluoro-4-[((S)-1-{1-[4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-benzonitrile 2063,5-Difluoro-4-[((S)-1-{1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanoyl}-piperidin-2-ylmethyl)-amino]-benzonitrile 2074-{[(S)-1-(1-Benzofuran-7-yl-methanoyl)-piperidin-2-ylmethyl]-amino}-3,5-difluoro-benzonitrile 2083,5-Difluoro-4-[((S)-1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-pyrrolidin-2-ylmethyl)-amino]-benzonitrile 2091-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-dimethylamino-5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 2101-(2-Amino-5-phenyl-thiazol-4-yl)-1-{(S)-2-[(5-bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 2111-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(3-methoxy-phenyl)-2-methyl-thiazol-4-yl]-methanone 2121-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(4-fluoro-phenyl)-thiophen-3-yl]-methanone 2131-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-pyridin-2-yl-phenyl)-methanone 2141-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-fluoro-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 2151-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(4-methoxy-phenyl)-thiophen-3-yl]-methanone 2161-{(S)-2-[(5-Ethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 2171-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 2181-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 2191-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methoxy-thiazol-4-yl]-methanone 2201-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-fluoro-2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 2211-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-phenyl-thiophen-3-yl)-methanone 2222′-(1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)methyl]-pyrrolidin-1-yl}-methanoyl)-biphenyl-4-carbonitrile 2231-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3-methoxy-phenyl)-thiophen-3-yl]-methanone 2241-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-pyrazol-1-yl-phenyl)-methanone 2251-{2-[((S)-1-{1-[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-pyrrolidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone 2261-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 2271-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 2281-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2[(5-methyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 2296-[((S)-1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]methanoyl}-pyrrolidin-2-ylmethyl)-amino]-nicotinonitrile 2305-(1-{2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-methanoyl-)4H-benzo[1,4]oxazin-3-one 2311-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-(2-piperidin-1-yl-ethyl)-1H-pyrazol-3-yl]-methanone 2321-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[1-(2-dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 2331-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-ethyl-5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 2341-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(6-methyl-2-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone2351-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(2-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 2361-{(S)-2-[(Dimethyl-trifluoromethyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 2371-{(S)-2-[(2,6-Dimethyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 2381-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(6-trifluoromethyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 2391-(3-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-morpholin-4-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 2401-(3-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-morpholin-4-yl)-1-[2-(4-fluoro-phenyl)-thiophen-3-yl]-methanone 2411-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(4-ethyl-quinolin-8-yl)-methanone 2421-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-isoquinolin-1-yl-methanone 2431-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2-methyl-quinolin-5-yl)-methanone 2441-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(3-methyl-quinolin-4-yl)-methanone 2451-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2,3-dichloro-phenyl)-methanone 2461-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(7-chloro-3-methyl-quinolin-8-yl)-methanone 2471-[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(5-chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 2481-{2-[((S)-1-{1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanoyl}-pyrrolidin-2-ylmethyl)-amino]-pyrimindin-5-yl}-ethanone 2491-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 2501-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(4-ethyl-quinolin-8-yl)-methanone 2511-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-dimethylamino-5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 2521-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2-pyridin-2-yl-phenyl)-methanone 2531-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-ethyl-5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 2541-Biphenyl-2-yl-1-{(S)-2-[(5-chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 2551-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-(2,3-dichloro-phenyl)-methanone 2561-{5-[3-(4-Chloro-butoxy)-phenyl]-2-methyl-thiazol-4-yl}-1-{(S)-2-[(5-chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 2571-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 2581-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 2591-{3-[(5-Bromo-pyridin-2-ylamino)-methyl]-morpholin-4-yl}-1-[2-(4-fluoro-phenyl)-thiophen-3-yl]-methanone 2601-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[2,4-dimethyl-quinolin-8-yl)-methanone 2611-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2-phenyl-quinolin-4-yl)-methanone 2621-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2-methyl-quinolin-4-yl)-methanone 2631-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(6-bromo-quinolin-4-yl)-methanone 2641-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(2-methyl-quinolin-8-yl)-methanone 2651-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-(8-bromo-quinolin-4-yl)-methanone 2661-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[1-(3-dimethylamino-propyl)-4-(4-fluorophenyl)-1H-pyrazol-3-yl]-methanone 2671-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[1-(2-dimethylamino-ethyl)-4-(4-fluorophenyl)-1H-pyrazol-3-yl]-methanone 2681-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-(2-piperidine-1-yl-ethyl)-1H-pyrazol-3-yl]-methanone 2691-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-(3-piperidine-1-yl-propyl)-1H-pyrazol-3-yl]-methanone 2701-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-piperidin-1-yl)-1-isoquinolin-1-yl-methanone 2711-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-piperidin-1-yl)-1-(2,3-dichloro-phenyl)-methanone 2721-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[2-dimethylaminomethyl-5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone 2731-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-piperidin-1-yl)-1-(3-methyl-quinolin-4-yl)-methanone 2741-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-piperidin-1-yl)-1-(2-methyl-quinolin-5-yl)-methanone 2751-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoneand pharmaceutically acceptable salts thereof.

Preferred compounds of formula (I) are selected from:

Example Compound Name 11-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-methyl-5-phenyl-thiazol-4-yl)-methanone 321-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 931-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-methanone 1051-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[(R)-2-(oxazolo[4,5-b]pyridin-2-ylaminomethyl)-piperidin-1-yl]-methanone 1061-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-{(R)-2-[(methyl-oxazolo[4,5-b]pyridin-2-yl-amino)-methyl]-piperidin-1-yl}-methanone 1076-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-methyl-amino]-nicotinonitrile 1081-((S)-2-{[(6,7-Difluoro-quinoxalin-2-yl)-methyl-amino]-methyl}-piperidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 1711-{2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone 1721-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-1-((S)-2-{[5-(1-hydroxy-ethyl)-pyrimidin-2-ylamino]-methyl}-piperidin-1-yl)-methanone 1732-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile 1743-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanoyl)-N-methyl-benzamide 1941-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 1951-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 1961-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone 1971-{(S)-2-[(5-Bromo-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 1981-{(S)-2-[(5-Bromo-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 2001-{3-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-morpholin-4-yl}-1-[4(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 2033,5-Difluoro-4-[((S)-1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-benzonitrile 2083,5-Difluoro-4-[((S)-1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-pyrrolidin-2-ylmethyl)-amino]-benzonitrile 2161-{(S)-2-[(5-Ethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 2171-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 2181-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone 2251-{2-[((S)-1-{1-[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-pyrrolidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone 2261-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 2271-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone 2281-[5-(4-Fluoro-phenyl)-2-methyl-thaizol-4-yl]-1-{(S)-2-[(5-methyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 2296-[((S)-1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanyol}-pyrrolidin-2-ylmethyl)-amino]-nicotinonitrile 2341-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(6-methyl-2-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone2351-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(2-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone 2391-(3-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-morpholin-4-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 2401-(3-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-morpholin-4-yl)-1-[2-(4-fluoro-phenyl)-thiophen-3-yl]-methanone 2491-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanoneand pharmaceutically acceptable salts thereof.

When a halogen atom is present in the compound of formula (I) it may befluorine, chlorine, bromine or iodine.

When the compound of formula (I) contains an alkyl group, whether aloneor forming part of a larger group, e.g. alkoxy or alkylthio, the alkylgroup may be straight chain, branched or cyclic, or combinationsthereof, it is preferably methyl or ethyl.

When used herein the term aryl means a 5- to 6-membered aromatic ringfor example phenyl, or a 7 to 12 membered bicyclic ring system where atleast one of the rings is aromatic for example naphthyl.

It will be appreciated that compounds of formula (I) may exist as R or Senantiomers. The present invention includes within its scope all suchisomers, including mixtures. Where additional chiral centres are presentin compounds of formula (I), the present invention includes within itsscope all possible diastereoismers, including mixtures thereof. Thedifferent isomeric forms may be separated or resolved one from the otherby conventional methods, or any given isomer may be obtained byconventional synthetic methods or by stereospecific or asymmetricsyntheses.

It will be understood that the invention includes pharmaceuticallyacceptable derivatives of compounds of formula (I) and that these areincluded within the scope of the invention.

Particular compounds according to the invention include those mentionedin the examples and their pharmaceutically acceptable derivatives.

As used herein “pharmaceutically acceptable derivative” includes anypharmaceutically acceptable salt, ester or salt of such ester of acompound of formula (I) which, upon administration to the recipient iscapable of providing (directly or indirectly) a compound of formula (I)or an active metabolite or residue thereof.

It will be appreciated that for use in medicine the salts of thecompounds of formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.Other salts e.g. oxalates, may be used, for example in the isolation ofcompounds of formula (I) and are included within the scope of thisinvention. Also included within the scope of the invention are solvatesand hydrates of compounds of formula (I).

Certain of the compounds of formula (I) may form acid addition saltswith one or more equivalents of the acid. The present invention includeswithin its scope all possible stoichiometric and non-stoichiometricforms.

Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions.

According to a further feature of the invention there is provided aprocess for the preparation of compounds of formula (I) and derivativesthereof. The following schemes detail some synthetic routes to compoundsof the invention.

wherein Ar¹, Ar², Y, m, p and R are as defined for formula (I), L¹ andL² are leaving groups, and P is a protecting group.

Examples of suitable leaving groups L¹ include halogen, hydroxy, OSO₂Me,OSO₂(4-tolyl). The reaction of (V) with (VI) preferably proceeds in aninert solvent such as N,N-dimethylformamide in the presence of a basesuch as triethylamine, sodium hydride or potassium t-butoxide.

Reaction of (VIII) with (IX) proceeds in an inert solvent such asdimethylformamide or xylene in the presence of a base such as potassiumcarbonate or diisopropylethylamine, preferably at elevated temperatures.

Alternatively where m is 1 and p is 0 or 1 compounds maybe prepared asshown in scheme 1c.

Reaction of (XI) with an alkylating agent (C₁₋₄)L¹ proceeds in thepresence of a base such as sodium hydride in an inert solvent such asdimethylformamide.

Examples of suitable leaving groups L² include halogen, hydroxy,OC(═O)alkyl and OC(═O)O-alkyl. The transformation (II) to (I) may becarried out in an inert solvent such as dichloromethane, in the presenceof a base such as triethylamine. Alternatively this step may be carriedout when L² represents hydroxy, in which case reaction with (II) takesplace in an inert solvent such as dichloromethane in the presence of adiimide reagent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, and an activator such as 1-hydroxybenzotriazole.

Examples of protecting groups P include t-butyloxycarbonyl,trifluoroacetyl, optionally substituted benzyl and benzyloxycarbonyl.Deprotection conditions are respectively, acid (e.g. trifluoroaceticacid in dichloromethane), base (e.g. sodium hydroxide in a solvent suchas aqueous methanol) and catalytic hydrogenolysis in an inert solvent(e.g using palladium on charcoal in a lower alcohol or ethyl acetate).

Compounds of formula (V), (VI) and (IX) are known in the literature orcan be prepared by known methods. Compounds (VIII) can be prepared byknown methods.

Within the schemes above there is scope for functional groupinterconversion; for example in compound (V), conversion of one value ofL¹ to another value of L¹; or in compounds (1V) conversion of protectinggroup P for another protecting group P, or conversion of one compound offormula (I) to another of formula (I) by interconversion ofsubstituents.

When R¹ is an aromatic group, the substituent R¹ may be introduced atthe final stage as illustrated in Scheme 2 by reaction of a compound offormula (VII) where L³ represents a leaving group such as halogen(preferably bromo or iodo) or trifluoromethylsulfonyloxy, and all othervariables are as previously defined, with a reagent R¹M, where M is theresidue of an organometallic species e.g. B(OH)₂ or trialkylstannyl.Such a process may be carried out in an inert solvent such as1,2-dimethoxyethane or 1,4-dioxan, in the presence of a transition metalcatalyst such as Pd(PPh₃)₄.

Wherein Y, Ar², m, p, Ar¹, R, R¹ and Y are as defined for compounds offormula (I). L³ is a leaving group.

The compounds of formula (I) may be prepared singly or as compoundlibraries comprising at least 2, e.g. 5 to 1000, preferably 10 to 100compounds of formula (I). Compound libraries may be prepared by acombinatorial ‘split and mix’ approach or by multiple parallel synthesisusing either solution phase or solid phase chemistry, by proceduresknown to those skilled in the art.

Thus according to a further aspect of the invention there is provided acompound library comprising at least 2 compounds of formula (I), orpharmaceutically acceptable derivatives thereof.

Pharmaceutically acceptable salts may be prepared conventionally byreaction with the appropriate acid or acid derivative.

The compounds of formula (I) and their pharmaceutically acceptablederivatives are useful for the treatment of diseases or disorders wherean antagonist of a human Orexin receptor is required such as obesity anddiabetes; prolactinoma; hypoprolactinemia; hypothalamic disorders ofgrowth hormone deficiency; idiopathic growth hormone deficiency;Cushings syndrome/disease; hypothalamic-adrenal dysfunction; dwarfism;sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lagsyndrome; sleep disturbances associated with diseases such asneurological disorders, neuropathic pain and restless leg syndrome;heart and lung diseases; depression; anxiety; addictions; obsessivecompulsive disorder; affective neurosis/disorder; depressiveneurosis/disorder; anxiety neurosis; dysthymic disorder; behaviourdisorder; mood disorder; sexual dysfunction; psychosexual dysfunction;sex disorder; sexual disorder; schizophrenia; manic depression;delirium; dementia; bulimia and hypopituitarism. Additionally thecompounds of formula (I) and pharmaceutically acceptable derivatives areuseful for the treatment of stroke, particularly ischemic orhaemorrhagic and/or in blocking an emetic response i.e. nausea andvomiting.

The compounds of formula (I) and their pharmaceutically acceptablederivatives are particularly useful for the treatment of obesity,including obesity associated with Type 2 diabetes, and sleep disorders.Additionally the compounds of formula (I) and pharmaceuticallyacceptable derivatives are useful for the treatment of stroke,particularly ischemic or haemorrhagic and/or in blocking an emeticresponse i.e. nausea and vomiting.

Other diseases or disorders which may be treated in accordance with theinvention include disturbed biological and circadian rhythms;adrenohypophysis disease; hypophysis disease; hypophysis tumor/adenoma;adrenohypophysis hypofunction; functional or psychogenic amenorrhea;adrenohypophysis hyperfunction; migraine; hyperalgesia; pain; enhancedor exaggerated sensitivity to pain such as hyperalgesia, causalgia andallodynia; acute pain; bum pain; atypical facial pain; neuropathic pain;back pain; complex regional pain syndromes I and II; arthritic pain;sports injury pain; pain related to infection e.g. HIV, post-poliosyndrome and post-herpetic neuralgia; phantom limb pain; labour pain;cancer pain; post-chemotherapy pain; post-stroke pain; post-operativepain; neuralgia; and tolerance to narcotics or withdrawal fromnarcotics.

The invention also provides a method of treating or preventing diseasesor disorders where an antagonist of a human Orexin receptor is required,which comprises administering to a subject in need thereof an effectiveamount of a compound of formula (I), or a pharmaceutically acceptablederivative thereof.

The invention also provides a compound of formula (I), or apharmaceutically acceptable derivative thereof, for use in the treatmentor prophylaxis of diseases or disorders where an antagonist of a humanOrexin receptor is required.

The invention also provides the use of a compound of formula (I), or apharmaceutically acceptable derivative thereof, in the manufacture of amedicament for the treatment or prophylaxis of diseases or disorderswhere an antagonist of a human Orexin receptor is required.

For use in therapy the compounds of the invention are usuallyadministered as a pharmaceutical composition. The invention alsoprovides a pharmaceutical composition comprising a compound of formula(I), or a pharmaceutically acceptable derivative thereof, and apharmaceutically acceptable carrier.

The compounds of formula (I) and their pharmaceutically acceptablederivatives may be administered by any convenient method, e.g. by oral,parenteral, buccal, sublingual, nasal, rectal or transdermaladministration, and the pharmaceutical compositions adapted accordingly.

The compounds of formula (I) and their pharmaceutically acceptablederivatives which are active when given orally can be formulated asliquids or solids, e.g. as syrups, suspensions, emulsions, tablets,capsules or lozenges.

A liquid formulation will generally consist of a suspension or solutionof the active ingredient in a suitable liquid carrier(s) e.g. an aqueoussolvent such as water, ethanol or glycerine, or a non-aqueous solvent,such as polyethylene glycol or an oil. The formulation may also containa suspending agent, preservative, flavouring and/or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations, such as magnesium stearate, starch, lactose, sucrose andcellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures, e.g. pellets containing the active ingredientcan be prepared using standard carriers and then filled into a hardgelatin capsule; alternatively a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), e.g. aqueousgums, celluloses, silicates or oils and the dispersion or suspensionthen filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe active ingredient in a sterile aqueous carrier or parenterallyacceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone,lecithin, arachis oil or sesame oil. Alternatively, the solution can belyophilised and then reconstituted with a suitable solvent just prior toadministration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active ingredient in apharmaceutically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container which can take the form of a cartridge or refill foruse with an atomizing device. Alternatively the sealed container may bea disposable dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve. Where the dosage formcomprises an aerosol dispenser, it will contain a propellant which canbe a compressed gas e.g. air, or an organic propellant such as afluorochlorohydrocarbon or hydrofluorocarbon. Aerosol dosage forms canalso take the form of pump-atomizers.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles where the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches.

Preferably the composition is in unit dose form such as a tablet,capsule or ampoule.

The dose of the compound of formula (I), or a pharmaceuticallyacceptable derivative thereof, used in the treatment or prophylaxis ofthe abovementioned disorders or diseases will vary in the usual way withthe particular disorder or disease being treated, the weight of thesubject and other similar factors. However, as a general rule, suitableunit doses may be 0.05 to 1000 mg, more suitably 0.05 to 500 mg. Unitdoses may be administered more than once a day for example two or threetimes a day, so that the total daily dosage is in the range of about0.01 to 100 mg/kg; and such therapy may extend for a number of weeks ormonths. In the case of pharmaceutically acceptable derivatives the abovefigures are calculated as the parent compound of formula (I).

No toxicological effects are indicated/expected when a compound offormula (I) is administered in the above mentioned dosage range.

Human Orexin-A has the amino acid sequence:

(SEQ ID NO:1) pyroGlu Pro Leu Pro Asp Cys Cys Arg Gln Lys Thr 1              5                 10 Cys Ser Cys Arg Leu Tyr Glu Leu LeuHis Gly Ala      15                         20 Gly Asn His Ala Ala GlyIle Leu Thr Leu-NH₂    25                 30

Orexin-A can be employed in screening procedures for compounds whichinhibit the ligand's activation of the orexin-1 receptor.

In general, such screening procedures involve providing appropriatecells which express the orexin-1 receptor on their surface. Such cellsinclude cells from mammals, yeast, Drosophila or E. coli. In particular,a polynucleotide encoding the orexin-1 receptor is used to transfectcells to express the receptor. The expressed receptor is then contactedwith a test compound and an orexin-1 receptor ligand to observeinhibition of a functional response. One such screening procedureinvolves the use of melanophores which are transfected to express theorexin-1 receptor, as described in WO 92/01810.

Another screening procedure involves introducing RNA encoding theorexin-1 receptor into Xenopus oocytes to transiently express thereceptor. The receptor oocytes are then contacted with a receptor ligandand a test compound, followed by detection of inhibition of a signal inthe case of screening for compounds which are thought to inhibitactivation of the receptor by the ligand.

Another method involves screening for compounds which inhibit activationof the receptor by determining inhibition of binding of a labelledorexin-1 receptor ligand to cells which have the receptor on theirsurface. This method involves transfecting a eukaryotic cell with DNAencoding the orexin-1 receptor such that the cell expresses the receptoron its surface and contacting the cell or cell membrane preparation witha compound in the presence of a labelled form of an orexin-1 receptorligand. The ligand may contain a radioactive label. The amount oflabelled ligand bound to the receptors is measured, e.g. by measuringradioactivity.

Yet another screening technique involves the use of FLIPR equipment forhigh throughput screening of test compounds that inhibit mobilization ofintracellular calcium ions, or other ions, by affecting the interactionof an orexin-1 receptor ligand with the orexin-1 receptor.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The following Examples illustrate the preparation of pharmacologicallyactive compounds of the invention. The Descriptions D1-D105 illustratethe preparation of intermediates to compounds of the invention.

In the Examples ¹H NMR's were measured at 250 MHz in CDCl₃ unlessotherwise stated.

Description 1: (S) 2-Aminomethyl-piperidine-1-carboxylic acid tert butylester a)2,2,2-Trifluoro-N-[(S)-1-((R)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-ylmethyl]-acetamide

(R)-2-[(S)-2-Aminomethyl-piperidin-1-yl])-2-phenyl-ethanol (20.0 g)(Froelich, Olivier; Desos, Patrice; Bonin, Martine; Quirion,Jean-Charles; Husson, Henri-Philippe; Zhu, Jieping., J. Org. Chem. 1996,61, 6700) and triethylamine (13.0 ml) were dissolved in dichloromethane(500 ml), cooled to 0° C. and trifluoroacetic anhydride (12.66 ml) addeddropwise. The mixture was warmed to room temperature and stirredovernight. The organic phase was washed with water, separated, dried andsolvent removed at reduced pressure. The residue was columnchromatographed [silica gel, 0-10% (9:1 methanol/ammonia) indichloromethane eluant] to give the title compound (28.0 g) as a yellowoil.

Mass Spectrum (API⁺): Found 331 (MH⁺). C₁₆H₂₁F₃N₂O₂ requires 330.

[α]_(D) −55@28° 1% in chloroform

b) 2,2,2-Trifluoro-N—(S)-1-piperidin-2-ylmethyl-acetamide

2,2,2-Trifluoro-N—[(S)-1-((R)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-ylmethyl]-acetamide(28.0 g) was dissolved in ethanol (200 ml) containing Pearlmans catalyst(2.0 g) and shaken under a hydrogen atmosphere (50 psi) at 50° C. for 3hours. The reaction mixture was filtered and solvent removed at reducedpressure. The residue was column chromatographed (silica gel, 0-10% (9:1methanol/ammonia) in dichloromethane eluant) to give the title compound(14.18 g) as a colourless oil.

Mass Spectrum (API⁺): Found 211 (MH⁺). C₈H₁₃F₃N₂O requires 210.

[α]_(D) +18@28° 1% in chloroform

¹H NMR δ: (d⁶-DMSO) 1.07 (1H, m), 1.32 (2H, m), 1.35-1.60 (2H, m), 1.72(1H, m), 2.54 (1H, t), 2.70 (1H, m), 3.00 (1H, d), 3.17 (3H, m), 9.30(1H, br. s.)

c)(S)-2-[(2,2,2-Trifluoro-ethanoylamino)-methyl]-piperidine-1-carboxylicacid tert butyl ester

2,2,2-Trifluoro-N—(S)-1-piperidin-2-ylmethyl-acetamide (14.18 g) wasdissolved in dichloromethane (250 ml) and treated with di-tert-butyldicarbonate (14.95 g). The mixture was stirred for 16 h, washed withwater, 2N hydrochloric acid and saturated brine, dried and solventremoved at reduced pressure to give the title compound (18.3 g)

Mass Spectrum (API⁺): Found 311 (MH⁺). C₁₃H₂₁F₃N₂O₃ requires 310.

[α]_(D) −94°@28° 1% in chloroform

¹H NMR δ: (d⁶-DMSO) 1.27 (1H, m), 1.36, 1.47 (9H, s), 1.49-1.58 (5H, m),2.88 (1H, m), 3.22 (1H, m), 3.49 (1H, m), 3.84 (1H, m), 4.34 (1H, m) and9.42 (1H, br. s.).

d) (S) 2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester

(S)-2-[(2,2,2-Trifluoro-ethanoylamino)-methyl]-piperidine-1-carboxylicacid tert butyl ester (18.2 g) was dissolved in methanol (500 ml) andtreated with potassium carbonate (16.1 g). After stirring for 16 hsolvent was removed at reduced pressure and the residue partitionedbetween dichloromethane/water. The organic phase was separated, washedwith brine, dried and solvent removed at reduced pressure. the residuewas column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) indichloromethane eluant) to give the title compound (8.82 g) ofdescription 1.

Mass Spectrum (API⁺): Found 215 (MH⁺). C₁₁H₂₂N₂O₂ requires 214.

[α]_(D) −32.2°@28° 1% in chloroform

¹H NMR δ: 1.44 (2H, m), 1.50 (9H, s), 2.64-2.80 (2H, m), 2.94 (1H, dd),3.99 (1H, m) and 4.15 (1H, m).

Description 2: (RS)2-(Benzoxazol-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butylester

(RS) 2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.21g) and 2-chlorobenzoxazole (0.153 g) and triethylamine (0.1 g) werecombined in tetrahydrofuran (10 ml) and stirred at room temperature for4 hours. The mixture was partitioned between ethyl acetate and water,the organic phase dried and solvent removed at reduced pressure to givethe title compound (0.36 g) as an oil that solidified on standing.

Mass Spectrum (API⁺): Found 332 (MH⁺). C₁₈H₂₅N₃O₃ requires 331.

Description 3: (RS) Benzoxazol-2-yl-piperidin-2-ylmethyl-amine

The compound of description 2 (0.36 g) was stirred in trifluoroaceticacid (10 ml) containing water (1 drop) for 3 hours. Solvent was removedat reduced pressure and the residue column chromatographed (silica gel,0-10% (9:1 methanol/ammonia) in dichloromethane eluant) to give thetitle compound (0.23 g).

Mass Spectrum (API⁺): Found 232 (MH⁺). C₁₃H₁₇N₃O requires 231.

Description 4:(R)-2-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-2-phenyl-ethanol

A mixture of (R)-2-[(S)-2-Aminomethyl-piperidin-1-yl])-2-phenyl-ethanol(1.0 g) (Froelich, Olivier; Desos, Patrice; Bonin, Martine; Quirion,Jean-Charles; Husson, Henri-Philippe; Zhu, Jieping. J. Org. Chem. 1996,61, 6700) and 2-chlorobenzoxazole (0.66 g) were combined intetrahydrofuran (40 ml) containing triethylamine (0.43 g) and stirred atroom temperature for 1 hours. The mixture was partitioned between ethylacetate and water, the organic phase separated, dried and solventremoved at reduced pressure. the residue was column chromatographed(silica gel, 30% pentane in ethyl acetate—ethyl acetate) to give thetitle compound (1.1 g).

¹H NMR δ: 1.59-1.71 (4H, m), 1.91 (1H, t), 2.73 (1H, m), 2.95 (1H, m),3.71 (2H, m), 4.0 (1H, m), 4.10 (1H, m), 4.26 (1H, m), 5.7 (1H, m), 7.03(1H, m), 7.17 (1H, m), 7.23-7.26 (3H, m) and 7.32-7.40 (4H, m). MassSpectrum (API⁺): Found 352 (MH⁺). C₂₁H₂₅N₃O₂ requires 351.

Description 5: Benzoxazol-2-yl-(S)-1-piperidin-2-ylmethyl-amine

The compound of description 4 (1.15 g) in ethanol (60 ml) containingPearlmans catalyst (0.23 g) was shaken under an atmosphere of hydrogen(50 psi) for 24 hours. Additional Pearlmans catalyst was added andshaking under hydrogen at 50 psi continued for a further 12 hours. Thereaction was filtered through kiesel guhr, the filtrate evaporated atreduced pressure and the residue column chromatographed (silica gel,ethyl acetate—ethyl acetate/methanol 1:1 eluant) to give the titlecompound (0.49 g) as an oil.

¹H NMR δ: 1.16-1.85 (7H, m), 2.64 (1H, m), 2.85-2.99 (1H, m), 3.11 (1H,m), 3.31 (1H, m), 3.55 (1H, m), 7.00 (1H, dd), 7.12 (1H, m), 7.20 (1H,d) and 7.30 (1H, m). Mass Spectrum (API⁺): Found 232 (MH⁺). C₁₃H₁₇N₃Orequires 231.

Description 6:(RS)-Benzoxazol-2-yl-(4-benzyl-morpholin-3-ylmethyl)-amine

From (4-benzyl-morpholin-3-yl)-methylamine (1 g) (Morie, Toshiya; Kato,Shiro; Harada, Hiroshi; Yoshida, Naoyuki; Fujiwara, Iwao; Matsumoto,Jun-ichi., Chem. Pharm. Bull. 1995, 43, 1137-47) and 2-chlorobenzoxazole(0.78 g), the title compound (0.77 g) was prepared according to themethod of D4.

¹H NMR δ: 2.33 (1H, m), 2.73-2.80 (2H, m), 3.33 (1H, d), 3.51-3.90 (6H,m), 4.10 (1H, d), 5.58 (1H, s), 7.04 (1H, m), 7.17 (1H, m) and 7.24-7.39(7H, m).

Mass Spectrum (API): Found 324 (MH⁺). C₁₉H₂₁N₃O₂ requires 323.

Description 7: (RS)-Benzoxazol-2-yl-morpholin-3-ylmethyl-amine

From the compound of D6 (0.77 g) the title compound (0.55 g) wasprepared according to the method of D5.

¹H NMR δ: 2.93-3.23 (2H, m), 3.46-4.03 (7H, m), 6.95-7.23 (4H, m). MassSpectrum (API⁺): Found 234 (MH⁺). C₁₂H₁₅N₃O₂ requires 233.

Description 8: (RS)2-(1H-Benzoimidazol-2-ylaminomethyl)-piperidine-1-carboxylic acid tertbutyl ester

(RS)-2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.25g) and 2-chlorobenzimidazole (0.15 g) were combined and warmed to 100°C. for 48 hours. After cooling to room temperature the mixture wascolumn chromatographed (silica gel, ethyl acetate/pentane 1:4—ethylacetate/pentane 1:1 eluant) to give the title compound (0.1 g).

¹H NMR δ: 1.47 (9H, m), 1.65-1.81 (7H, m), 2.85 (1H, t), 3.47 (2H, m),3.91 (1H, d), 4.32 (1H, s), 5.78 (1H, s), 7.04 (3H, m) and 7.29 (1H, s).

Mass Spectrum (API⁺): Found 331 (MH⁺). C₁₈H₂₆N₄O₂ requires 330.

Description 9: (RS)-(1H-Benzoimidazol-2-yl)-piperidin-2-ylmethyl-aminedihydrochloride

The compound of D8 (0.39 g) was stirred in a mixture of 4M HCl indioxan/methanol (1:1) for 4 hours. Solvent was removed at reducedpressure to give the title compound (0.28 g) as a foam.

Mass Spectrum (API⁺): Found 231 (MH⁺). C₁₃H₁₈N₄ requires 230.

Description 10: (RS)2-(Quinolin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butylester

The title compound (0.1 g) was prepared from (RS)2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.5 ml) and2-chloroquinoline (0.5 g) according to the procedure of D8. MassSpectrum (API⁺): Found 342 (MH⁺). C₂₀H₂₇N₃O₂ requires 341.

Description 11: (RS)-Piperidin-2-ylmethyl-quinolin-2-yl-amine

The title compound (0.29 g) was prepared from the compound of D10according to the method of D9. After removal of solvent the residue wasdissolved in dichloromethane, washed with saturated sodium hydrogencarbonate, the organic phase separated, dried and solvent removed atreduced pressure to give the title compound.

¹H NMR δ: 1.20-1.96 (6H, m), 2.64 (1H, m), 2.85 (1H, m), 3.10 (1H, m),3.35 (1H, m), 3.60 (1H, m), 5.17 (1H, m), 6.66 (1H, d), 7.19 (1H, dt),7.48-7.58 (2H, m), 7.66 (1H, d) and 7.78 (1H, d).

Mass Spectrum (API⁺): Found 242 (MH⁺). C₁₅H₁₉N₃ requires 241.

Description 12:(RS)-2-(Benzothiazol-2-ylaminomethyl)-piperidine-1-carboxylic acid tertbutyl ester

The title compound (1.2 g) after column chromatography (silica gel, 5%diethyl ether/hexane—diethyl ether eluant) was prepared from (RS)2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) and2-chlorobenzothiazole (1.58 g) according to the method of D2.

Mass Spectrum (API⁺): Found 348 (MH⁺). C₁₈H₂₅N₃O₂S requires 347.

Description 13: (RS)—Benzothiazol-2-yl-piperidin-2-ylmethyl-amine

The compound of D12 (1.2 g) was dissolved in methanol (60 ml) andtreated with 4N HCl in dioxan (12 ml). the mixture was stirred for 4 h,added to water containing sodium hydrogen carbonate and extracted withethyl acetate (×3). The combined organic phase was dried and solventremoved at reduced pressure to give the title compound (0.70 g).

Mass Spectrum (API⁺): Found 348 (MH⁺). C₁₃H₁₇N₃S requires 347.

Description 14:2-(RS)-(Isoquinolin-1-ylaminomethyl)-piperidine-1-carboxylic acid tertbutyl ester

The title compound (0.76 g) was prepared from (RS)2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1.6 ml) and1-chloroisoquinoline (0.8 g) according to the method used for thepreparation of the compound of D8.

Mass Spectrum (API⁺): Found 342 (MH⁺). C₂₀H₂₇N₃O₂ requires 341.

Description 15: Isoquinolin-1-yl-piperidin-2-ylmethyl-amine

The title compound (0.39 g) was prepared according to the method ofdescription 13 from the compound of D14 (0.75 g).

Mass Spectrum (API⁺): Found 242 (MH⁺). C₁₅H₁₉N₃ requires 241.

Description 16: (S) 2-(Quinolin-2-ylaminomethyl)-piperidine-1-carboxylicacid tert butyl ester

The title compound (0.1 μg) was prepared from (S)2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1.23 g) and2-chloroquinoline (1 g) according to the procedure of D8.

Mass Spectrum (API⁺): Found 342 (MH⁺). C₂₀H₂₇N₃O₂ requires 341.

Description 17: (S)-Piperidin-2-ylmethyl-quinolin-2-yl-amine

The compound of D16 (0.11 g) was dissolved in dichloromethane (10 ml)and trifluoroacetic acid (1 ml) added. The mixture was stirred for 4 h,poured into ice containing potassium carbonate and extracted with 10%methanol/dichloromethane (×3). The combined organic extracts were driedand solvent removed at reduced pressure to give the title compound (0.05g).

Mass Spectrum (API⁺): Found 242 (MH⁺). C₁₅H₁₉N₃ requires 241.

Description 18: (RS)2-(Quinoxalin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butylester

The title compound (0.73 g) was prepared from (RS)2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1 ml) and2-chloroquinoxaline (0.5 g) according to the procedure of D8. MassSpectrum (API⁺): Found 343 (MH⁺). C₁₉H₂₆N₄O₂ requires 342

Description 19: (RS)-Piperidin-2-ylmethyl-quinoxalin-2-yl-amine

The title compound (0.36 g) was prepared from the compound of D18 (0.71g) according to the method of D17.

Mass Spectrum (API⁺): Found 243 (MH⁺). C₁₄H₁₈N₄ requires 242.

Description 20: (RS)2-(Pyrimidin-2-ylaminomethyl)-piperidine-1-carboxylic acid tert butylester

A mixture of (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butylester (1.28 g) and 2-chloropyrimidine was heated at 100° C. for 48hours. After cooling to room temperature the mixture was columnchromatographed (silica gel, 0-10% (9:1 methanol/ammonia) indichloromethane eluant) to give the title compound (0.42 g) as an oil.

Mass Spectrum (API⁺): Found 293 (MH⁺). C₁₅H₂₄N₄O₂ requires 292.

Description 21: (RS)-Piperidin-2-ylmethyl-pyrimidin-2-yl-amine

The title compound (0.350 g) was prepared from the compound of D20 (0.4g) according to the method of D17.

Mass Spectrum (API⁺): Found 193 (MH⁺). C₁₀H₁₆N₄ requires 192.

Description 22: (RS) 2-(Pyrazin-2-ylaminomethyl)-piperidine-1-carboxylicacid tert butyl ester

The title compound (0.18 g) was prepared from (RS)2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.54 g) and2-chloropyrazine according to the method of D20.

Mass Spectrum (API⁺): Found 293 (MH⁺). C₁₅H₂₄N₄O₂ requires 292.

Description 23: (RS)-Piperidin-2-ylmethyl-pyrazin-2-yl-amine

The title compound (0.18 g) was prepared from the compound of D22 (0.08g) according to the method of D17.

Mass Spectrum (API⁺): Found 193 (MH⁺). C₁₀H₁₆N₄ requires 192.

Description 24:(S)-2-(Quinazolin-4-ylaminomethyl)-piperidine-1-carboxylic acid tertbutyl ester

(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 g),4-chloroquinoxaline (0.768 g) and diisopropylethylamine (0.816 ml) weredissolved in tetrahydrofuran (75 ml) and heated to reflux for 6 hoursunder an atmosphere of argon. After cooling, the reaction solution waspartitioned between ethyl acetate and water. The organic layer waswashed with saturated sodium hydrogen carbonate solution, saturatedbrine, dried and evaporated. The residue was chromatographed over silicagel, eluting with a gradient of 50 to 100% ethyl acetate in hexane. Thetitle compound was obtained as a white foam (1.44 g).

¹H NMR δ: 1.40 (3H, s), 2.90 (1H, dt), 3.35-3.50 (1H, br.), 3.9-4.05(1H, br.), 4.15-4.3 (1H, br.), 4.68-4.82 (1H, br.), 6.9-7.2 (1H, br.),7.40 (1H, t), 7.65-7.85 (3H, m), 8.65 (1H, s).

Description 25: (S)-2-(Quinazolin-4-ylaminomethyl)-piperidine

(S)-2-(Quinazolin-4-ylaminomethyl)-piperidine-1-carboxylic acid tertbutyl ester (1.2 g) was dissolved in trifluoroacetic acid (60 ml) andstirred at room temperature for 2 hours. The solution was thenevaporated and the residue chromatographed over silica gel, eluting with0 to 10% (9:1 methanol—concentrated ammonia solution) indichloromethane. The title compound was obtained as a white foam (0.84g), MH⁺ 243.

Description 26:(S)-2-[(6,7-Difluoro-3-methylquinoxalin-2-ylamino)methyl]-piperidine-1-carboxylicacid tert buty ester

(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.14g), and 2-chloro-6,7-difluoro-3-methylquinoxaline Teng et al PCT Int.Appl (2000), WO00/42026A1 20000720 (1.14 g) were dissolved in DMF (2 ml)and heated to 90° C. for 3 days under an atmosphere of argon. Aftercooling, the reaction solution was partitioned between ethyl acetate andwater. The organic layer was washed with water, saturated brine, driedand evaporated. The residue was chromatographed over silica gel, elutingwith a gradient of 10 to 50% ethyl acetate in hexane. The title compoundwas obtained as a pink foam (0.524 g), MH⁺ 393.

Description 27:(S)-2-[(6,7-Difluoro-3-methylquinoxalin-2-ylamino)methyl]-piperidine

(S)-2-[(6,7-Difluoro-3-methylquinoxalin-2-ylamino)methyl]-piperidine-1-carboxylicacid tert butyl ester (0.524 g) was dissolved in trifluoroacetic acid(15 ml) and stirred at room temperature for 3 hours. The solution wasthen evaporated and the residue chromatographed over silica gel, elutingwith 0 to 10% (9:1 methanol—concentrated ammonia solution) indichloromethane. The title compound was obtained as a white solid (0.289g), MH⁺ 293.

Description 28:(S)-2-[(6,7-Difluoroquinoxalin-2-ylamino)methyl]-piperidine-1-carboxylicacid tert buty ester

(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.607g), and 2-chloro-6,7-difluoroquinoxaline McQuaid et. al. J. Med. Chem.(1992), 35(18), 3319-24 (0.569 g) were dissolved in dimethylformamide (1ml) and heated to 90° C. for 5 days under an atmosphere of argon. Aftercooling, the reaction solution was partitioned between ethyl acetate andwater. The organic layer was washed with water, saturated brine, driedand evaporated. The residue was chromatographed over silica gel, elutingwith a gradient of 10 to 50% ethyl acetate in hexane. The title compoundwas obtained as a pale yellow solid (0.460 g), MH⁺ 379.

Description 29:(S)-2-[(6,7-Difluoroquinoxalin-2-ylamino)methyl]-piperidine

(S)-2-[(6,7-Difluoroquinoxalin-2-ylamino)methyl]-piperidine-1-carboxylicacid tert butyl ester (0.460 g) was dissolved in trifluoroacetic acid(10 ml) and stirred at room temperature for 3 hours. The solution wasthen evaporated and the residue chromatographed over silica gel, elutingwith 0 to 10% (9:1 methanol—concentrated ammonia solution) indichloromethane. The title compound was obtained as a pale yellow foam(0.286 g), MH⁺ 279.

Description 30:(R,S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidine-1-carboxylicacid tert butyl ester

(R,S)-2-Aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.0g) and 2-chloro-6,7-difluoroquinoxaline (3.0 g) were combined in xylene(20 ml) containing diisopropylethylamine (3 ml) and heated at 130° C.for 24 hours. Solvent was removed at reduced pressure and the residuecolumn chromatographed (silica gel, diethyl ether:petroleum ether 1:1)to give the title compound (3.4 g)

Mass Spectrum (API⁺): Found 365 (MH⁺). C₁₈H₂₂F₂N₄O₂ requires 364.

Description 31:(R,S)-2-[(6,7-Difluoroquinoxalin-2-ylamino)methyl]-pyrrolidine

The compound of D30 (3.4 g) was dissolved in dichloromethane (100 ml)and treated with trifluoroacetic acid (15 ml). After 3 h additionaltrifluoroacetic acid (40 ml) and dichloromethane (100 ml) was added. Themixture was stirred for 48 h, poured into excess aqueous sodium hydrogencarbonate, the organic phase separated, dried and solvent removed atreduced pressure. The residue was column chromatographed (silica gel, 5%(9:1 methanol/ammonia)/dichloromethane to give the title compound (0.9g) Mass Spectrum (API⁺): Found 265 (MH⁺). C₁₃H₁₄F₂N₄ requires 264. ¹HNMR δ: 1.56 (1H, m), 1.72-1.93 (3H, m), 2.96 (2 h, m), 3.28 (1H, m),3.49 (1H, m), 3.64 (1H, m), 7.39 (1H, dd), 7.59 1H, dd) and 8.16 (1H,s).

Description 32:(S)-2-(quinazolin-2-ylamino)methyl-piperidine-1-carboxylic acid tertbutyl ester

The title compound (0.6 g) was prepared from(S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.68 g)and 2-chloroquinazoline (0.53 g) according to the method of D30.

Mass Spectrum (API⁺): Found 343 (MH⁺). C₁₉H₂₆N₄O₂ requires 342.

Description 33: (S)-1-Piperidin-2-ylmethyl-quinazolin-2-yl-amine

The title compound (0.384 g) was prepared from the compound of D32 (0.6g) according to the method of D31

Mass Spectrum (API⁺): Found 243 (MH⁺). C₁₄H₁₈N₄ requires 242.

¹H NMR δ: 1.18-1.65 6H, m), 2.66 (1H, m), 3.08-3.23 (2H, m), 3.50 (1H,m), 3.69 (1H, m), 6.16 (1 h, br. s), 7.20 (1H, t), 7.54-7.69 (3H, m) and8.91 (1H, s).

Description 34:(S)-2-([1,5]Naphthyridin-2-ylaminomethyl)-piperidine-1-carboxylic acidtert butyl ester

The title compound (0.48 g) was prepared from(S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.59 g)and 2-chloro-1,5-naphthyridine Rapoport, et al J Org. Chem. (1971),36(3), 450-4 (0.40 g) according to the method of D30.

Mass Spectrum (API⁺): Found 343 (MH⁺). C₁₉H₂₆N₄O₂ requires 342.

Description 35: [1,5]Naphthyridin-2-yl-(S)-1-piperidin-2-ylmethyl-amine

The title compound (0.30 g) was prepared from the compound of D34 (0.48g) according to the method of D31.

Mass Spectrum (API⁺): Found 243 (MH⁺). C₁₄H₁₈N₄ requires 242.

¹H NMR δ: 1.25-1.88 (6H, m), 2.68 (1H, m), 2.98 (1H, m), 3.16 (1H, m),3.37-3.50 (1H, m), 3.66 (1H, m), 6.85 (1H, d), 7.41 1H, dd), 7.95 (1H,t) and 8.58 (1H, m).

Description 36:(S)-2-(1,8-Naphthyridin-2-ylamino)methyl-piperidine-1-carboxylic acidtert butyl ester

The title compound (0.28 g) was prepared from(S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.35 g)and 2-chloro-1,8-naphthyridine (0.19 g) according to the method of D30.

Mass Spectrum (API⁺): Found 343 (MH⁺). C₁₉H₂₆N₄O₂ requires 342.

Description 37: [1,8]Naphthyridin-2-yl-(S)-1-piperidin-2-ylmethyl-amine

The title compound (0.11 g) was prepared from the compound of D36 (0.28g) according to the method of D31.

Mass Spectrum (API⁺): Found 243 (MH⁺). C₁₄H₁₈N₄ requires 242.

Description 38: (RS)2-(4-Azabenzooxazol-2-ylaminomethyl)-piperidine-1-carboxylic acid tertbutyl ester

The title compound (0.7 g) was prepared from(RS)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.64g) and 2-methylthio-4-azabenzoxazole Chu-Moyer et al J. Org. Chem.(1995), 60(17), 5721-5. (0.5 g)according to the method of D30.

Mass Spectrum (API⁺): Found 333 (MH⁺). C₁₇H₂₄N₄O₃ requires 332.

Description 39:(RS)-Oxazolo[4,5-b]]pyridin-2-yl-piperidin-2-ylmethyl-amine

The title compound (0.55 g) was prepared from the compound of D38 (0.7g) according to the method of D31.

Mass Spectrum (API⁺): Found 233 (MH⁺). C₁₂H₁₆N₄O requires 232.

Description 40:((S)-1-{1-[2-(3-Methyl-[1,2,4]-oxadiazol-5-yl)-phenyl]-methanoyl}-piperidin-2-ylmethyl)-carbamicacid tert butyl ester

A mixture of (S)-1-piperidin-2-ylmethyl-carbamic acid tert butyl ester(2.0 g) and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoic acid (1.9) indimethylformaide (10 ml containing diisopropylethylamine (2.4 ml) wastreated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate] (3.55 g) and stirred at 90° C. for 16 hours.Solvent was removed at reduced pressure and the residue columnchromatographed (silica gel, diethyl ether eluant) to give the titlecompound (3.4 g).

Mass Spectrum (API⁺): Found 401 (MH⁺). C₂₁H₂₈N₄O₄ requires 400.

Description 41:1-((S)-2-Aminomethyl-piperidin-1-yl)-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone

The title compound (0.53 g) was prepared from the compound of D40according to the method of D13.

Mass Spectrum (API⁺): Found 301 (MH⁺). C₁₆H₂₀N₄O₂ requires 300.

Description 42:Methyl-((S)-1-{1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanoyl}-piperidin-2-ylmethyl)-carbamicacid dimethyl-ethyl ester

((S)-1-{1-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanoyl}-piperidin-2-ylmethyl)-carbamicacid tert butyl ester (0.4 g) in tetrahydrofuran (5 ml) was treated withsodium hydride (0.1 g). After evolution of hydrogen had ceasediodomethane (0.1 ml) was added and the reaction stirred for 16 hours.The reaction was quenched with ice/water, extracted with diethyl ether(×3), the combined organic extracts dried and solvent removed at reducedpressure. The residue was column chromatographed (silica gel, diethylether) to give the title compound (0.2 g).

Mass Spectrum (API⁺): Found 415 (MH⁺). C₂₂H₃₀N₄O₄ requires 414.

Description 43:1-[(R)-2-Methylaminomethyl-piperidin-1-yl])-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone

The title compound (0.15 g) was prepared from the compound of D42according to the method of D13.

Mass Spectrum (API⁺): Found 315 (MH⁺). C₁₁H₁₂N₄ requires 314.

Description 44:(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidine-1-carboxylicacid tert butyl ester

The title compound (0.53 g) was prepared from(S)-2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g)and 2-chloro-6,7-difluoroquinoxaline (0.5 g) according to the method ofD30.

Mass Spectrum (API⁺): Found 365 (MH⁺). C₁₈H₂₂F₂N₄O₂ requires 364.

Description 45:(S)-2-[(6,7-Difluoroquinoxalin-2-ylamino)methyl]-pyrrolidine

The title compound (0.38 g) was prepared from the compound of D44 (0.53g) according to the method of D31.

Mass Spectrum (API⁺): Found 265 (MH⁺). C₁₃H₁₄F₂N₄ requires 264.

Description 46:(RS)-3-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-morpholine-4-carboxylicacid tert butyl ester

The title compound (0.58 g) was prepared from2-aminomethylmorpholine-4-carboxylic acid tert-butyl ester (0.82 g) and2-chloro-6,7-difluoroquinoxaline (0.76 g) according to the method ofD30.

Mass Spectrum (API⁺): Found 381 (MH⁺). C₁₈H₂₂F₂N₄O₃ requires 380.

Description 47:(6,7-Difluoro-quinoxalin-2-yl)-morpholin-3-ylmethyl-amine

The compound of D46 (0.58 g) was dissolved in trifluoroacetic acid andstirred for 3 hours. Solvent was removed at reduced pressure and theresidue partitioned between aqueous sodium hydrogen carbonate and ethylacetate. The organic phase was separated dried, solvent removed atreduced pressure and the residue column chromatographed (silica gel,0-10% (9:1 methanol/ammonia) in dichloromethane, eluant) to give thetitle compound (0.327 g).

Mass Spectrum (API⁺): Found 281 (MH⁺). C₁₃H₁₄F₂N₄O requires 280.

Description 48:2-(Pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidine-1-carboxylic acidtert butyl ester and2-(Pyrido[2,3-b]-pyrazin-3-ylaminomethyl)-piperidine-1-carboxylic acidtert butyl ester

A mixture of (S)-2-aminomethyl-piperidine-1-carboxylic acid tert butylester (1.0 g) and a 2:1 mixture of 2-chloro-pyrido[2,3-b]pyrazine and3-chloro-pyrido[2,3-b]pyrazine (0.8 g) was combined and warmed to 90° C.for 18 hours. The mixture was diluted with ethyl acetate, washed withaqueous sodium hydrogen carbonate and water, the organic phase dried andsolvent was removed at reduced pressure. The residue was columnchromatographed (silica gel, dichloromethane 0 to 6% ethanol indichloromethane, 1% increments) to give as the faster running component2-(pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidine-1-carboxylic acidtert butyl ester (0.48 g). mass spectrum (API⁺): Found 344 (MH⁺).C₁₇H₂₅N₅O₂ requires 343 and2-(pyrido[2,3-b]pyrazin-3-ylaminomethyl)-piperidine-1-carboxylic acidtert butyl ester (0.3 g) mass spectrum (API⁺): Found 344 (MH⁺).C₁₇H₂₅N₅O₂ requires 343.

Description 49: Piperidin-2-ylmethyl-pyrido[2,3-b]pyrazin-2-yl-aminetrifluoroacetate salt

2-(Pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidine-1-carboxylic acidtert butyl ester (0.48 g) was dissolved in dichloromethane (3 ml),cooled (ice bath) and treated with trifluoroacetic acid (2 ml). Themixture was stirred for 3 hours at room temperature, solvent removed atreduced pressure and the residue co-evaporated with toluene to give thetitle compound (0.45 g).

Mass spectrum (API⁺): Found 244 (MH⁺). C₁₃H₁₇N₅ requires 243.

Description 50: Piperidin-2-ylmethyl-pyrido[2,3-b]pyrazin-3-yl-aminetrifluoroacetate salt

The title compound (0.3 g) was prepared from2-(pyrido[2,3-b]pyrazin-3-ylaminomethyl)-piperidine-1-carboxylic acidtert butyl ester (0.3 g) according to the method of description 49

Mass spectrum (API⁺): Found 244 (MH⁺). C₁₃H₁₇N₅ requires 243.

Description 51: 2-Thioureidomethyl-piperidine-1-carboxylic acid tertbutyl ester

Benzoyl chloride (1.2 ml) was added dropwise to sodium thiocyanate (0.90g) in acetone (50 ml). When the addition was complete the mixture wasrefluxed for 15 minutes, cooled to room temperature and (RS)2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (2.0 g) inacetone (5 ml) added. The mixture was refluxed for 2 hours, cooled toroom temperature and solvent removed at reduced pressure. The residuewas column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) indichloromethane eluant) to give the title product (1.95 g).

Mass spectrum (API⁺): Found 274 (MH⁺). C)₂H₂₃N₃O₂S requires 273.

Description 52:2-[(4-Phenyl-thiazol-2-ylamino)-methyl]-piperidine-1-carboxylic acidtert butyl ester

The compound of description 51 (1.95 g) was dissolved in ethanol (100ml) containing triethylamine (0.99 ml). Phenacyl bromide (1.42 g) wasadded and the mixture stirred for 16 hours. Solvent was removed atreduced pressure and the residue partitioned between ethyl acetate andwater. The organic phase was separated and solvent removed at reducedpressure. The residue was column chromatographed (silica gel,dichloromethane eluant) to give the title compound (2.42 g).

Mass spectrum (API⁺): Found 274 (MH⁺). C₂₀H₂₇N₃O₂S requires 273.

Description 53: (4-Phenyl-thiazol-2-yl)-piperidin-2-ylmethyl-amine

The title compound (1.55 g) was prepared from the compound of D52 (2.42g) according to the method of D47.

Mass spectrum (API⁺): Found 174 (MH⁺). C₁₅H₁₉N₃O₂S requires 173.

Description 54:2-[(5-Cyano-pyridin-2-ylamino)-methyl]-piperidine-1-carboxylic acid tertbutyl ester

The title compound (1.54 g) was prepared from(S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (2.0 g)and 2-chloro-5-cyanopyridine (1.29 g) in the presence ofdiisopropylethylamine (1.21 g) according to the method of D28.

Mass spectrum (API⁺): Found 317 (MH⁺). C₁₇H₂₄N₄O₂ requires 316.

Description 55: 6-[(Piperidin-2-ylmethyl)-amino]-nicotinonitrile

The title compound (1.56 g) was prepared from the compound of D54 (1.53g) and trifluoroacetic acid according to the method of D29.

Mass spectrum (API⁺): Found 217 (MH⁺). C)₂H₁₆N₄ requires 216.

Description 56:2-[(4-Trifluoromethyl-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylicacid tert butyl ester

The title compound (0.298 g) was prepared from(S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 g)and 2-chloro-4-trifluoropyrimidine (0.85 g) according to the method ofD28.

Mass spectrum (API⁺): Found 361 (MH⁺). C₁₆H₂₃F₃N₄O₂ requires 360.

Description 57:Piperidin-2-ylmethyl-(4-trifluoromethyl-pyrimidin-2-yl)-amine

The title compound (0.25 g) was prepared from the compound of D56 (0.29g) and trifluoroacetic acid according to the method of D29.

Mass spectrum (API⁺): Found 261 (MH⁺). C₁₁H₁₅F₃N₄ requires 260.

Description 58:((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-carbamicacid tert butyl ester

The title compound (3.96 g) was prepared from(S)-1-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.14 g) and4-(4-fluoro-phenyl)-1-methyl-1 H-pyrazol-3-yl carboxylic acid (2.20 g)according to the method of D40.

Mass spectrum (API⁺): Found 417 (MH⁺). C₂₂H₂₉FN₄O₃ requires 416.

Description 59:((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-methyl-carbamicacid dimethyl-ethyl ester

The title compound (2.0 g) was prepared from the compound of description58 (3.85 g) according to the method of D42.

Mass spectrum (API⁺): Found 431 (MH⁺). C₂₃H₃₁FN₄O₃ requires 430

Description 60:1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-1-((S)-2-methylaminomethyl-piperidin-1-yl)-methanone

The title compound (0.15 g) was prepared for the compound of D59 (0.50g) according to the method of D29.

Description 61:(S)-2-[(3-Cyano-pyridin-2-ylamino)-methyl]-piperidine-1-carboxylic acidtert butyl ester

The title compound (0.66 g) was prepared from(S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.55 g)and 2-chloro-3-cyanopyridine (1.0 g) according to the method of D28.

Mass spectrum (API⁺): Found 317 (MH⁺). C₁₇H₂₄N₄O₂ requires 316

Description 62: 2-[((S)-1-Piperidin-2-ylmethyl)-amino]-nicotinonitrile

The title compound (0.53 g) was prepared from the compound of D61 (0.663g) and trifluoroacetic acid according to the method of D29.

Mass spectrum (API⁺): Found 217 (MH⁺). C₁₂H₁₆N₄ requires 216

Description 63:(S)-2-[(4-Cyano-pyridin-2-ylamino)-methyl]-piperidine-1-carboxylic acidtert butyl ester

The title compound (0.24 g) was prepared from(S)-2-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.14 g)and 2-chloro-4-cyanopyridine (0.74 g) according to the method of D28.

Mass spectrum (API⁺): Found 317 (MH⁺). C₁₇H₂₄N₄O₂ requires 316

Description 64: 4-Cyano-2-[((S)-1-Piperidin-2-ylmethyl)-amino]-pyridine

The title compound (0.17 g) was prepared from the compound of D63 (0.243g) and trifluoroacetic acid according to the method of D29.

Mass spectrum (API⁺): Found 217 (MH⁺). C₁₂H₁₆N₄ requires 216

Description 65:(S)2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidine-1-carboxylic acidtert butyl carbonate

(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1 g),5-bromo-2-chloropyrimidine (0.9 g) were combined in xylene (20 ml)containing potassium carbonate (1.29 g) and diisopropylethylamine (2.43g) and warmed to reflux for 48 h. The mixture was cooled to roomtemperature, filtered and solvent removed at reduced pressure. Theresidue was column chromatographed (silica gel, pentane—25% ethylacetate/pentane). The appropriate fractions were collected, solventremoved at reduced pressure to give the title compound (1.43 g) as acolourless gum

Mass spectrum (API⁺): Found 272 (MH⁺-tert BOC). C₁₀H₁₄N₄Br requires 371

Description 66: (S) (5-Bromo-pyrimidin-2-yl)-piperidin-2-ylmethyl-amine

The title compound (1.40 g) was prepared from the compound of D65 (2.1g) according to the method of D9.

Mass spectrum (API⁺): Found 272 (MH⁺). C₁₀H₁₄N₄Br requires 271.

Description 67: (S)2-[(3-Cyano-6,7-difluoro-quinolin-2-ylamino)-methyl]-piperidine-1-carboxylicacid tert butyl ester

(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.1 g)and 2-chloro-3-cyano-5,6-difluoroquinoline (1.12 g) according to themethod of D28 were combined in xylene (15 ml) containing potassiumcarbonate (4.0 g) and diisopropylethylamine (4 ml) and boiled for 20hours. The reaction mixture was cooled to room temperature, filtered andsolvent removed at reduced pressure. The residue was columnchromatographed (silica gel, dichloromethane eluant) to give aftercombining appropriate fractions the title compound (1.8 g).

Mass spectrum (API⁺): Found 403 (MH⁺). C₂₁H₂₄F₂N₄O₂ requires 402

Description 68: (S)6,7-Difluoro-2-[(piperidin-2-ylmethyl)-amino]-quinoline-3-carbonitrile

The title compound (1.40 g) was prepared from the compound of D67 (1.8g) according to the method of D9.

Mass spectrum (API⁺): Found 303 (MH⁺). C₁₆H₁₆F₂N₄ requires 302

Description 69:(S)2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-carboxylic acidtert butyl carbonate

(S)-2-Aminomethyl-pyrrolidine-1-carboxylic acid tert butyl ester (2 g),5-bromo-2-chloropyrimidine (1.93 g) were combined in xylene (40 ml)containing potassium carbonate (2.76 g) and diisopropylethylamine (5.23ml) and warmed to reflux for 20 h. The mixture was cooled to roomtemperature, filtered and solvent removed at reduced pressure. Theresidue was column chromatographed (silica gel, pentane—25% ethylacetate/pentane). The appropriate fractions were collected, solventremoved at reduced pressure to give the title compound (1.78 g) as acolourless gum

Mass spectrum (API⁺): Found 257 (MH⁺-tert BOC). C₁₋₄H₂₁BrN₄O₂ requires357

Description 70: (S) (5-Bromo-pyrimidin-2-yl)-pyrrolidin-2-ylmethyl-amine

The title compound (1.40 g) was prepared from the compound of D69 (1.78g) according to the method of D9.

Mass spectrum (API⁺): Found 258 (MH⁺). C₉H₁₂N₄Br requires 257.

Description 71:3-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanoyl)-benzoicacid

3-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanoyl)-benzoicacid methy ester (0.5 g) was dissolved in methanol (15 ml) and treatedwith 1M sodium hydroxide (1.7 ml). The reaction mixture was stirred for12 h, additional 1M sodium hydroxide (1.7 ml) added and stirringcontinued for a further 24 h. The reaction mixture was diluted withwater and washed with ethyl acetate. The aqueous phase was acidifiedwith 2M hydrochloric acid and extracted with ethyl acetate (×3). thecombined organic phase was dried (MgSO₄), fioltered and solvent removedat reduced pressure to give the title compound (0.463 g) as a yellowsolid.

Mass spectrum (API⁺): Found 427 (MH⁺). C₂₂H₂₀F₂N₄O₃ requires 426.

Description 72: 1,1,1-Trifluoromethanesulphonic acid,5-bromo-pyridin-2-yl ester

To a solution of 5-bromo-2-pyridone (3 g) in dichloromethane (60 ml) andpyridine (60 ml) at 0° C. under argon was added dropwisetrifluoromethane sulphonic anhydride (5.4 g). The resulting mixture waswarmed to ambient temperature and after 20 h was evaporated and theresidue chromatographed on silica gel eluting with ethyl acetate toafford the title product (3.5 g) as a yellow oil. ¹H NMR δ: 7.10 (1H, d,J=8 Hz), 8.00 (1H, dd, 2.4 and 8 Hz), 8.46 (1H, d, J=2.4 Hz).

Description 73:(S)-2-[(5-Bromopyridin-2-ylamino)-methyl]-pyrrolidine-1-carboxylic acidtert-butyl ester

The title product (0.22 g) was obtained from(S)-2-aminomethyl-pyrrolidine-1-carboxylic acid tert butyl ester (1 g)and the compound of D72 (1.7 g) according to the method of D69. MassSpectrum (Electrospray LC/MS), API⁺: Found 356 (MH⁺). C₁₅H₂₂ ⁷⁹BrN₃O₂requires 355.

Description 74: (5-Bromo-pyridin-2-yl)-(S)-1-pyrrolidin-2-ylmethylamine

To a solution of the compound from D73 (0.49 g) in dichloromethane (40ml) at ambient temperature was added trifluoroacetic acid (5 ml). After48 h, the reaction mixture was evaporated and partitioned betweenchloroform and 1M sodium hydroxide. The aqueous layer was extracted withchloroform and the combined organic extracts dried and evaporated toafford the title compound (0.33 g) as an orange oil. ¹H NMR δ: 1.44-1.48(1H, m), 1.71-1.81 (3H, m), 2.05 (1H, br s), 2.93 (2H, m), 3.09-3.13(1H, m), 3.35-3.41 (2H, m), 4.99 (1H, br s), 6.32 (1H, d, J=9 Hz), 7.43(1H, dd, J=3 and 9 Hz), 8.08 (1H, d, J=3 Hz).

Description 75:N-(4-Benzyl-morpholin-3-ylmethyl)-2,2,2-trifluoroacetamide

To (4-benzyl-morpholin-3-yl)-methylamine (7.34 g) in dichloromethane(240 ml) was added triethylamine (5.83 ml), followed by dropwiseaddition of trifluoroacetic anhydride (8.23 g) over 25 min at 0° C.under argon. The reaction mixture was allowed to reach ambienttemperature and after stirring for 18 h, was diluted in dichloromethaneand washed with saturated aqueous sodium hydrogencarbonate. The organicphase was separated, dried and evaporated to afford a brown gum that waspurified on silica gel, eluting with ethyl acetate-pentane mixtures toafford the title product (5.17 g) as an orange gum. Mass Spectrum(API⁺): Found 303 (MH⁺). C₁₄H₁₇F₃N₂O₂ requires 302.

Description 76: 2,2,2-Trifluoro-N-morpholin-3-ylmethyl acetamide

To the compound from D75 (1.62 g) in methanol (40 ml) was addedpalladium black (0.45 g) and formic acid (10 drops) and the mixturestirred at ambient temperature for 16 h. Further palladium black (0.225g) and formic acid (10 drops) were added and after 1 h, the reactionmixture was filtered through kieselguhr and the filtrate evaporated toan orange gum. Re-evaporation from dichloromethane provided the titlecompound (1.4 g) as a pink solid. Mass Spectrum (API⁺): Found 213 (MH⁺).C₇H₁₁F₃N₂O₂ requires 212.

Description 77:3-[(2,2,2-Trifluoro-ethanoylamino)-methyl]-morpholine-4-carboxylic acidtert-butyl ester

A mixture of the compound from D76 (1.75 g), triethylamine (2.25 ml) anddi-tert-butyl dicarbonate (3.59 g) in dichloromethane (75 ml) wasstirred at ambient temperature for 18 h. The reaction mixture wasdiluted with dichloromethane and washed successively with 2Mhydrochloric acid, water and brine, dried and evaporated to a gum.Chromatography on silica gel eluting with ethyl acetate-pentane mixturesafforded the title compound (1.70 g) as a pale yellow solid. MassSpectrum (API⁺): Found 213 (MH-^(t)Boc)⁺. C₁₂H₁₉F₃N₂O₄ requires 312.

Description 78: 3-Aminomethyl-morpholine-4-carboxylic acid tert-butylester

A mixture of the compound from D77 (1.7 g) and potassium carbonate (3.77g) in methanol (80 ml) and water (27 ml) was stirred at ambienttemperature for 4 h and then heated at 50° C. for a further 2 h. Thereaction mixture was concentrated to remove methanol, diluted with waterand extracted with ethyl acetate (×3) and dichloromethane (×4). Thecombined extracts were dried and evaporated to afford the title product(0.97 g) as a yellow gum. Mass Spectrum (API⁺): Found 116 (MH-^(t)Boc)⁺.C₁₂H₂₀N₂O₃ requires 216.

Description 79:3-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-morpholine-4-carboxylc acidtert-butyl ester

The title compound (1.19 g) was obtained from the compound of D78 (0.97g) and 5-bromo-2-chloropyrimidine (0.87 g) according to the method ofD30. Mass spectrum (API⁺): Found 273 (MH-^(t)Boc). C₁₄H₂₁ ⁷⁹BrN₄O₃requires 372.

Description 80: (5-Bromo-pyrimidin-2-yl)-morpholin-3-ylmethyl amine

To the compound of D79 (1.15 g) in dichloromethane (45 ml) at 0° C. wasadded trifluoroacetic acid (5 ml) and the reaction mixture then stirredat ambient temperature for 2 h. The resulting solution was poured ontoice and saturated aqueous potassium carbonate solution, and thenextracted with dichloromethane (×2). The organic extracts were dried andevaporated to afford the title product (0.85 g) as an off white solid.Mass Spectrum (API⁺): Found 273 (MH⁺). C₉H₁₃ ⁷⁹BrN₄O requires 272.

Description 81:(S)-2-[(4-Cyano-2,6-difluoro-phenylamino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester

(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.36 g)and 3,4,5-trifluorobenzonitrile (1.00 g) were heated under argon inxylene (10 ml) containing diisopropylethylamine (3.3 ml) for 16 h. Thereaction mixture was cooled and partitioned between ethyl acetate andwater. The organic phase was washed with brine, dried and evaporated togive a solid which was triturated with pentane-ether to afford the titleproduct (0.16 g) as an off white powder. Chromatography of the motherliquors on silica gel eluting with ethyl acetate-pentane mixturesafforded further title product (0.92 g). Mass Spectrum (API⁺): Found 252(MH⁺-^(t)Boc). C₁₈H₂₃F₂N₃O₂ requires 351.

Description 82:3,5-Difluoro-4-[((S)-1-piperidin-2-ylmethyl)-amino]-benzonitrile

Trifluoroacetic acid (3 ml) was added to a solution of D81 (1.05 g) indichloromethane (27 ml) at 0° C. The reaction was allowed to reachambient temperature, stirred for 4 h and then poured into saturatedaqueous potassium carbonate. The aqueous phase was extracted withdichloromethane and the combined extracts dried and evaporated to affordthe title compound (0.59 g) as an off white solid. Mass Spectrum (API⁺):Found 252 (MH⁺). C₁₃H₁₅F₂N₃ requires 251.

Description 83:(S)-2-[(4-Cyano-2,6-difluoro-phenylamino)-methyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

The title compound (0.295 g) was obtained from(S)-2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.402g) and 3,4,5-trifluorobenzonitrile (0.314 g) using a similar procedureto that described in Description 81. Mass Spectrum (API⁺): Found 238(MH⁺-^(t)Boc) C₁₇H₂₁F₂N₃O₂ requires 337.

Description 84:3,5-Difluoro-4-[((S)-1-pyrrolidin-2-ylmethyl)-amino]-benzonitrile

The title compound (0.19 g) was obtained from the compound of D83 (0.28g) using a similar procedure to that described in Description 82.

Description 85:(S)-2-[(5-Ethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

The title compound (0.10 g) was obtained from(S)-2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.75g) and 2-chloro-5-ethyl pyrimidine (0.53 g) using a similar procedure tothat described in description 81. Mass Spectrum (Electrospray LC/MS):Found 307 (MH⁺). C₁₆H₂₆N₄O₂ requires 306.

Description 86:(5-Ethyl-pyrimidin-2-yl)-(S)-1-pyrrolidin-2-ylmethylamine

The title compound (0.07 g) was obtained from the compound of D85 (0.10g) using the method of D9. Mass Spectrum (Electrospray LC/MS): Found 207(MH⁺). C₁₁H₁₈N₄ requires 206.

Description 87:(S)-2-[(2,2,2-Trifluoro-ethanoylamino)-methyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

To a solution of (S)-2-aminomethyl pyrrolidine-1-carboxylic acidtert-butyl ester (1.3 g) in dichloromethane (50 ml) containingtriethylamine (1.4 ml) was added trifluoroacetic anhydride (1.6 g)dropwise under argon. After 16 h at ambient temperature the reactionmixture was diluted with dichloromethane and washed with brine. Theaqueous layer was extracted with dichloromethane and the combinedextracts dried and evaporated. Chromatography of the residue on silicagel eluting with pentane-ethyl acetate mixtures afforded the titlecompound (1.43 g) as an orange oil. ¹H NMR δ: 1.30-1.50 (1H, m), 1.47(9H, s), 1.60-1.75 (1H, m), 1.80-1.95 (2H, m), 2.00-2.10 (1H, m),3.22-3.30 (1H, m), 3.30-3.55 (3H, m), 9.03 (1H, br s).

Description 88:(S)-2-{[Methyl-(2,2,2-trifluoro-ethanoyl)-amino]-methyl}-pyrrolidine-1-carboxylicacid tert-butyl ester

Sodium hydride (0.23 g, 60% dispersion in oil) was added to a solutionof the compound of D87 (1.4 g) in dimethylformamide (30 ml) under argon.After 1 h, iodomethane (0.32 ml) was added and the reaction mixturestirred for a further 16 h before being partitioned between ethylacetate and water. The aqueous layer was extracted with ethyl acetateand the combined extracts washed with brine, dried and evaporated togive the title compound (1.6 g) as an orange oil. Mass Spectrum (API⁺):Found 311 (MH⁺). C₁₃H₂₁F₃N₂O₃ requires 310.

Description 89: (S)-2-Methylaminomethyl-pyrrolidine-1-carboxylic acidtert-butyl ester

A mixture of the compound of D88 (1.47 g) and 1M potassium carbonate (20ml) in methanol (50 ml) was stirred at ambient temperature for 20 h.After removal of the methanol in vacuo, the residue was partitionedbetween chloroform and water. The aqueous layer was extracted withchloroform and the combined extracts dried and evaporated to afford thetitle product (0.82 g) as an orange oil.

Description 90:(S)-2-1{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidine-201-carboxylicacid tert-butyl ester

The title product (0.85 g) was obtained from the compound of D89 (0.82g) and 5-bromo-2-chloro pyrimidine (0.77 g) in a similar manner to thatdescribed in the procedure of description 81. Mass Spectrum (API⁺):Found 371 (MH⁺). C₁₅H₂₃ ⁷⁹BrN₄O₂ requires 370.

Description 91:(5-Bromo-pyrimidin-2-yl)-methyl-(S)-1-pyrrolidin-2-yl)methylamine

A solution of the compound from D90 (0.82 g) in dichloromethane (50 ml)and trifluoroacetic acid (10 ml) was stirred at ambient temperature for20 h. evaporated and partitioned between ethyl acetate and 1M sodiumhydroxide. The organic phase was separated, dried and evaporated toafford the title product as an orange oil (0.54 g). Mass Spectrum(API⁺): Found 271 (MH⁺). C₁₀H₁₅ ⁷⁹BrN₄ requires 270.

Description 92:(S)-2-[(5-Acetyl-pyrimidin-2-ylamino)-methyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

The title compound (0.57 g) was prepared from the compound of D69 (1.06g) (1-ethoxyvinyl)tributyl tin (1.2 ml) and tetrakis(triphenylphosphine)palladium (0) (0.172 g) according to the method ofExample 171. Mass Spectrum (API⁺): Found 321 (MH⁺). C₁₆H₂₄N₄O₃ requires320.

Description 93:1-{2-[((S)-1-Pyrrolidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanonetrifluoroacetate

To a solution of the compound of D92 (0.57 g) in dichloromethane (18 ml)at 0° C. was added trifluoroacetic acid (2 ml) dropwise. The reactionmixture was stirred at ambient temperature for 2 h, and evaporated toafford the title compound as a yellow gum (1.13 g).

Mass Spectrum (API⁺): Found 221 (MH⁺). C₁₁H₁₆N₄O requires 220.

Description 94:(S)-2-[((5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

(S)-2-Aminomethyl pyrrolidine-1-carboxylic acid tert-butyl ester (3.38g), 2,5-dichloropyrimidine (2.50 g), potassium carbonate (4.67 g) anddiisopropylethylamine (8.79 ml) were heated in xylene (60 ml) at 100° C.for 3.75 h. The cooled reaction mixture was filtered and the filtrateevaporated to a gum which was chromatographed on silica gel, elutingwith ethyl acetate-pentane fractions, to afford the title compound as apale yellow solid (2.55 g). Mass Spectrum (API⁺). Found 213(MH⁺-^(t)Boc). C₃₄H₂₁ ³⁵ClN₄O₂ requires 312.

Description 95:(5-Chloro-pyrimidin-2-yl)-(S)-1-pyrrolidin-2-ylmethylamine

The compound of D94 (2.5 g) was dissolved in dichloromethane (63 ml),cooled to 0° C. and trifluoroacetic acid (7 ml) added dropwise. Thereaction mixture was stirred at ambient temperature for 2 h, recooled to0° C. and further trifluoroacetic acid (3 ml) added. After 2 h atambient temperature the mixture was carefully poured into ice-saturatedpotassium carbonate and the organic layer separated. The aqueous phasewas extracted with dichloromethane (×4) and the combined extracts driedand evaporated to afford the title product (1.74 g) as an orange solid.Mass Spectrum (Electrospray LC/MS): Found 213 (MH⁺). C₉H₁₃ ³⁵ClN₄requires 212.

Description 96:(S)-2-[(5-Cyano-pyridin-2-ylamino)-methyl]-pyrrolidine-1-carboxylic acidtert-butyl ester

(S)-2-Aminomethyl pyrrolidine-1-carboxylic acid tert-butyl ester (0.3g), 6-chloronicotinonitrile (0.21 g), potassium carbonate (0.41 g) anddiisopropylethylamine (0.78 ml) were heated in xylene at 130° C. for 26h, cooled and the mixture filtered through kieselguhr. The filtrate wasevaporated and the residue chromatographed on silica gel, eluting withethyl acetate-hexane mixtures to afford the title compound (0.2 g). MassSpectrum (API⁺): Found 303 (MH⁺). C₁₆H₂₂N₄O₂ requires 302.

Description 97: 6-[((S)-1-Pyrrolidin-2-ylmethyl)-amino]-nicotinonitrile

A solution of the compound of D96 (0.2 g) in dichloromethane (20 ml) andtrifluoroacetic acid (2.5 ml) was stirred at ambient temperature for 2h., evaporated and partitioned between dichloromethane and 1M sodiumhydroxide. The aqueous phase was extracted with dichloromethane and thecombined extracts dried and evaporated to afford the title compound as agum (0.137 g). Mass Spectrum (Electrospray LC/MS): Found 203 (MH⁺).C₁₁H₄N₄ requires 202.

Description 98: 1,1,1-Trifluoromethanesulfonic acid6-methyl-2-methylsulfanyl-pyrimidin-4-yl ester

To a solution of 6-methyl-2-methylsulfanyl-pyrimidin-4-ol (1 g) indichloromethane (40 ml) containing triethylamine (1.35 ml) at 0° C.under argon was added trifluoromethanesulphonic anhydride (1.46 ml)dropwise. The resulting solution was allowed to reach ambienttemperature and stirred for 16 h. before being partitioned betweendichloromethane and saturated aqueous sodium hydrogen carbonatesolution. The organic phase was washed with brine, dried and evaporatedand the residue chromatographed on silica gel, eluting with ethylacetate-pentane mixtures, to afford the title compound (0.8 g). ¹H NMRδ: 2.53 (3H, s), 2.55 (3H, s), 6.63 (1H, s).

Description 99: 2,2,2-Trifluoro-N—(S)-1-pyrrolidin-2-ylmethyl-acetamide

The title compound (2.31 g) was obtained from the compound of D87 (5.5g) using the method of D97. ¹H NMR δ: 1.30-1.50 (1H, m), 1.70-1.95 (3H,m), 2.20 (1H, br s), 2.85-2.90 (1H, m), 2.94-2.97 (1H, m), 3.07-3.12(1H, m), 3.37-3.39 (1H, m), 3.44-3.48 (1H, m), 7.15 (1H, br s).

Description 100:2,2,2-Trifluoro-N—((S)-1-{1-[5-(4-fluorophenyl)-2-methyl-thiazol-4-yl]-methanoyl}-pyrrolidin-2-ylmethyl)-acetamide

The title compound (3.84 g) was obtained from the compound of D99 (2.3μg) and 5-(4-fluorophenyl)-2-methyl-thiazole-4-carboxylic acid (3.08 g)using the method of Example 229. Mass Spectrum (Electrospray LC/MS):Found 416 (MH⁺). C₁₈H₁₇F₄N₃O₂S requires 415.

Description 101:1-((S)-2-Aminomethyl-pyrrolidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (2.45 g) was obtained from the compound of D100 (3.84g) using a similar procedure to that described in D78. Mass Spectrum(Electrospray LC/MS): Found 320 (MH⁺). C₁₆H₁₈FN₃OS requires 319.

Description 102:3-[(2,2,2-Trifluoro-ethanoylamino)-methyl]-morpholine-4-carboxylic acidtert-butyl ester

The title compound (0.56 g) was obtained from the compound of D77 (0.55g) and iodomethane (0.12 ml) using a method similar to that ofDescription 88. Mass Spectrum (API⁺): Found 227 (MH⁺-^(t)Boc).C₁₃H₂₁F₃N₂O₄ requires 326.

Description 103: 3-Methylaminomethyl-morpholine-4-carboxylic acidtert-butyl ester

The title compound (0.29 g) was obtained from the compound of D 102(0.56 g) using the method of Description 89.

Description 104:3-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-morpholine-4-carboxylicacid tert-butyl ester

The title compound (0.3 g) was obtained from the compound of D103 (0.29g) and 5-bromo-2-chloropyrimidine (0.26 g) using the method ofDescription 81. Mass Spectrum (Electrospray LC/MS): Found 287(MH⁺-^(t)Boc). C₁₅H₂₃ ⁷⁹BrN₄O₃ requires 386.

Description 105:(5-Bromo-pyrimidin-2-yl)-methyl-morpholin-3-ylmethyl-amine

The title compound (0.19 g) was obtained from the compound of D104 (0.3g) according to the method of Description 91. Mass Spectrum (API⁺):Found 287 (MH⁺). C₁₀H₁₅ ⁷⁹BrN₄O requires 286.

EXAMPLE 11-[2-(Benzoxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-methyl-5-phenyl-thiazol-4-yl)-methanone

The amine of D3 (0.11 g), triethylamine (0.05 g) and2-methyl-5-phenyl-thiazole-4-carbonyl chloride (0.12 g) were combined indichloromethane (5 ml) and shaken for 16 hours. The organic phase waswashed with water, filtered through a Whatman phase-separation filtertube, solvent removed at reduced pressure to give after columnchromatography (silica gel, 0-10% (9:1 methanol/ammonia) indichloromethane eluant) the title compound (0.13 g). Mass Spectrum(API⁺): Found 433 (MH⁺). C₂₄H₂₄N₄O₂S requires 432.

The compounds of the Examples below were prepared from the appropriateamine and acid chloride using a similar procedure to that described inExample 1.

Mass Spectrum (Electrospray LC/MS) Example Amine Y Ar² Ar¹ API⁺ 2 D3 CH₂

Found 412 (MH⁺).C₂₆H₂₅N₃O₂ requires 411 3 D3 CH₂

Found 418 (MH⁺).C₂₃H₂₃N₅O₃ requires 417 4 D3 CH₂

Found 420 (MH⁺).C₂₁H₂₀F₃N₃O₃ requires 419 5 D3 CH₂

Found 386 (MH⁺).C₂₄H₂₃N₃O₂ requires 385 6 D3 CH₂

Found 366 (MH⁺).C₂₁H₂₃N₃O₃ requires 365 7 D3 CH₂

Found 462 (MH⁺).C₂₀H₂₀IN₃O₂ requires 461 8 D5 CH₂

Found 420 (MH⁺).C₂₁H₂₀F₃N₃O₃ requires 419 9 D5 CH₂

Found 418 (MH⁺).C₂₃H₂₃N₅O₃ requires 417 10 D5 CH₂

Found 412 (MH⁺).C₂₆H₂₅N₃O₂ requires 411 11 D5 CH₂

Found 462 (MH⁺).C₂₀H₂₀IN₃O₂ requires 461 12 D3 CH₂ Ph

Found 336 (MH⁺).C₂₀H₂₁N₃O₂ requires 335 13 D9 CH₂

Found 450 (MH⁺).C₂₄H₂₄FN₅OS requires 449 14 D9 CH₂

Found 417 (MH⁺).C₂₃H₂₄N₆O₂ requires 416 15 D13 CH₂

Found 434 (MH⁺).C₂₃H₂₃N₅O₂S requires 433 16 D13 CH₂

Found 436 (MH⁺).C₂₁H₂₀F₃N₃O₂S requires 435 17 D13 CH₂

Found 428 (MH⁺).C₂₆H₂₅N₃OS requires 427 18 D13 CH₂

Found 449 (MH⁺).C₂₄H₂₄N₄OS₂ requires 448 19 D15 CH₂

Found 461 (MH⁺).C₂₆H₂₅FN₄OS requires 460 20 D15 CH₂

Found 428 (MH⁺).C₂₅H₂₅N₅O₂ requires 427 21 D15 CH₂

Found 430 (MH⁺).C₂₃H₂₂F₃N₃O₂ requires 429 22 D15 CH₂

Found 472 (MH⁺).C₂₂H₂₂IN₃O requires 471 23 D15 CH₂

Found 396 (MH⁺).C₂₆H₂₅N₃O requires 395 24 D19 CH₂

Found 431 (MH⁺).C₂₂H₂₁F₃N₄O₂ requires 430 25 D19 CH₂

Found 431 (MH⁺).C₂₂H₂₁F₃N₄O₂ requires 430 26 D19 CH₂

Found 473 (MH⁺).C₂₁H₂₁IN₄O requires 472 27 D19 CH₂

Found 462 (MH⁺).C₂₅H₂₄FN₅OS requires 461 28 D19 CH₂

Found 429 (MH⁺).C₂₄H₂₄N₆O₂ requires 428 29 D33 CH₂

Found 462 (MH⁺).C₂₄H₂₄FN₅OS requires 461 30 D35 CH₂

Found 462 (MH⁺).C₂₅H₂₄FN₅OS requires 461 31 D37 CH₂

Found 462 (MH⁺).C₂₅H₂₄FN₅OS requires 461

EXAMPLE 321-[(S)-2-(Benzoxazol-2-ylaminomethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

A mixture of amine D5 (0.05 g), 2-methyl-5-phenyl-thiazole-4-carboxylicacid (0.026 g) and diisopropylethylamine (0.06 ml) in dimethylformamide(5 ml) was treated with[O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate] (0.042 g) and the mixture stirred for 48 hours. Themixture was diluted with ethyl acetate, washed with sodium hydrogencarbonate and water, dried, solvent removed at reduced pressure and theresidue column chromatographed (silica gel, dichloromethane—1%methanol/dichloromethane) to give the title compound (0.05 g).

Mass Spectrum (API⁺): Found 451 (MH⁺). C₂₄H₂₃FN₄O₂S requires 450.

The compounds of the Examples below were prepared from the appropriateamine and acid using similar procedures to that described in Example 32.

Mass Spectrum (Electrospray LC/MS), Example Amine Y Ar² Ar¹ API⁺ 33 D7 O

Found 420 (MH⁺).C₂₂H₂₁N₅O₄ requires 419 34 D11 CH₂

Found 461 (MH⁺).C₂₆H₂₅FN₄OS requires 460 35 D11 CH₂

Found 428 (MH⁺).C₂₅H₂₅N₅O₂ requires 427Prepared as the HCl salt 36 D11CH₂

Found 430 (MH⁺).C₂₃H₂₂F₃N₃O₂ requires429Prepared as the HCl salt 37 D13CH₂

Found 402 (MH⁺).C₂₄H₂₃N₃OS requires 401 38 D17 CH₂

Found 461 (MH⁺).C₂₆H₂₅FN₄OS requires 460 39 D21 CH₂

Found 412 (MH⁺).C₂₁H₂₂FN₅OS requires 411 40 D21 CH₂

Found 379 (MH⁺).C₂₀H₂₂N₆O₂ requires 378 41 D23 CH₂

Found 412 (MH⁺).C₂₁H₂₂FN₅OS requires 411 42 D25 CH₂

Found 462 (MH⁺).C₂₅H₂₄FN₅OS requires 461 43 D25 CH₂

Found 448 (MH⁺).C₂₄H₂₂FN₅OS requires 447 44 D25 CH₂

Found 445 (MH⁺).C₂₅H₂₅FN₆O requires 444 45 D25 CH₂

Found 445 (MH⁺).C₂₅H₂₅FN₆O requires 444 46 D25 CH₂

Found 431 (MH⁺).C₂₄H₂₃FN₆O requires 430 47 D25 CH₂

Found 462 (MH⁺).C₂₅H₂₄FN₅OS requires 461 48 D25 CH₂

Found 446 (MH⁺).C₂₄H₂₄FN₇O requires 445 49 D25 CH₂

Found 397 (MH⁺).C₂₅H₂₄N₄O requires 396 50 D25 CH₂

Found 456 (MH⁺).C₂₂H₂₃ ⁷⁹BrN₄O₂ requires 455 51 D25 CH₂

Found 429 (MH⁺).C₂₄H₂₄N₆O₂ requires 428 52 D25 CH₂

Found 431 (MH⁺).C₂₂H₂₁F₃N₄O₂ requires 430 53 D27 CH₂

Found 512 (MH⁺).C₂₆H₂₄F₃N₅OS requires 511 54 D27 CH₂

Found 498 (MH⁺).C₂₅H₂₂F₃N₅OS requires 497 55 D27 CH₂

Found 495 (MH⁺).C₂₆H₂₅F₃N₆O requires 494 56 D27 CH₂

Found 481 (MH⁺).C₂₅H₂₃F₃N₆O requires 480 57 D27 CH₂

Found 495 (MH⁺).C₂₆H₂₅F₃N₆O requires 494 58 D27 CH₂

Found 495 (MH⁺).C₂₆H₂₅F₃N₆O requires 494 59 D27 CH₂

Found 447 (MH⁺).C₂₆H₂₄F₂N₄O requires 446 60 D29 CH₂

Found 434 (MH⁺).C₂₄H₂₁F₂N₅O requires 433 61 D29 CH₂

Found 482 (MH⁺).C₂₅H₂₂F₃N₅O₂ requires 481 62 D29 CH₂

Found 498 (MH⁺).C₂₅H₂₂F₃N₅OS requires 497 63 D29 CH₂

Found 465 (MH⁺).C₂₄H₂₂F₂N₆O₂ requires 464 64 D29 CH₂

Found 467 (MH⁺).C₂₂H₁₉F₅N₄O₂ requires 466 65 D29 CH₂

Found 459 (MH⁺).C₂₇H₂₄F₂N₄O requires 458 66 D29 CH₂

Found 491 (MH⁺).C₂₂H₂₁ ⁷⁹BrF₂N₄O₂ requires 490 67 D29 CH₂

Found 481 (MH⁺).C₂₅H₂₃F₃N₆O requires 480 68 D29 CH₂

Found 481 (MH⁺).C₂₅H₂₃F₃N₆O requires 480 69 D29 CH₂

Found 482 (MH⁺).C₂₄H₂₂F₃N₇O requires 481 70 D29 CH₂

Found 433 (MH⁺).C₂₅H₂₂F₂N₄O requires 432 71 D29 CH₂

Found 484 (MH⁺).C₂₄H₂₀F₃N₅OS requires 483 72 D33 CH₂

Found 445 (MH⁺).C₂₅H₂₅FN₆O requires 444 73 D39 CH₂

Found 419 (MH⁺).C₂₂H₂₂N₆O₃ requires 418 74 D39 CH₂

Found 421 (MH⁺).C₂₀H₁₉F₃N₄O₃ requires 420 75 D39 CH₂

Found 452 (MH⁺).C₂₃H₂₂FN₅O₂S requires 451 76 D39 CH₂

Found 463 (MH⁺).C₁₉H₁₉IN₄O₂ requires 462 77 D47 O

Found 500 (MH⁺).C₂₄H₂₀F₃N₅O₂S requires 499 78 D47 O

Found 483 (MH⁺).C₂₄H₂₁F₃N₆O₂ requires 482 79 D47 O

Found 483 (MH⁺).C₂₄H₂₁F₃N₆O₂ requires 482 80 D49 CH₂

Found 463 (MH⁺).C₂₄H₂₃FN₆OS requires 462 81 D50 CH₂

Found 463 (MH⁺).C₂₄H₂₃FN₆OS requires 462 82 D53 CH₂

Found 493 (MH⁺).C₂₆H₂₅FN₄OS₂ requires 492 83 D29 CH₂

Found 435 (MH⁺).C₂₃H₂₀F₂N₆O requires 434 84 D29 CH₂

Found 434 (MH⁺).C₂₄H₂₁F₂N₅O requires 433 85 D29 CH₂

Found 434 (MH⁺).C₂₄H₂₁F₂N₅O requires 433 86 D29 CH₂

Found 414 (MH⁺).C₂₁H₂₁F₂N₅O₂ requires 413 87 D29 CH₂

Found 435 (MH⁺).C₂₃H₂₀F₂N₆O requires 434 88 D55 CH₂

Found 419 (MH⁺).C₂₃H₂₃FN₆O requires 418 89 D57 CH₂

Found 480 (MH⁺).C₂₂H₂₁F₄N₅OS requires 479 90 D49 CH₂

Found 388 MH⁺).C₂₁H₂₁N₇O requires 387 91 D29 CH₂

Found 527 (MH⁺).C₂₆H₂₅F₃N₆OS requires 526 92 D29 CH₂

Found 484 (MH⁺).C₂₆H₃₁F₂N₅O₂ requires 483 109 D29 CH₂

Found 441 (MH⁺).C₂₃H₁₉F₃N₄O₂ requires 440 110 D62 CH₂

Found 436 (MH⁺).C₂₃H₂₂FN₅OS requires 435 111 D62 CH₂

Found 403 (MH⁺).C₂₂H₂₂N₆O₂ requires 402 112 D64 CH₂

Found 436 (MH⁺).C₂₃H₂₂FN₅OS requires 435 113 D29 CH₂

Found 439 (MH⁺).C₂₃H₂₀F₂N₄OS requires 438 114 D29 CH₂

Found 423 (MH⁺).C₂₂H₂₀F₂N₆O requires 422 115 D29 CH₂

Found 424 (MH⁺).C₂₁H₁₉F₂N₇O requires 423 116 D29 CH₂

Found 440 (MH⁺).C₂₂H₁₉F₂N₅OS requires 439 117 D29 CH₂

Found 452 (MH⁺).C₂₁H₁₈Cl₂F₂N₄O requires 451 118 D29 CH₂

Found 443 (MH⁺).C₂₃H₂₄F₂N₄O₃ requires 442 121 D49 CH₂

Found 399 (MH⁺).C₂₃H₂₂N₆O requires 398 122 D49 CH₂

Found 387 (MH⁺).C₂₂H₂₂N₆O requires 386 123 D49 CH₂

Found 399 (MH⁺).C₂₃H₂₂N₆O requires 398 124 D29 CH₂

Found 525 (MH⁺).C₂₇H₂₇F₃N₆O₂ requires 524 125 D29 CH₂

Found 418 (MH⁺).C₂₀H₂₁F₂N₅OS requires 417 126 D29 CH₂

Found 482 (MH⁺).C₂₄H₂₂F₃N₇O requires 481 127 D55 CH₂

Found 463 (MH⁺).C₂₅H₂₇FN₆O₂requires 462 128 D66 CH₂

Found 490 (MH⁺).C₂₁H₂₁ ⁷⁹BrFN₅OSrequires 489 129 D66 CH₂

Found 459 (MH⁺).C₂₀H₂₀ ⁷⁹BrFN₆Orequires 458 130 D66 CH₂

Found 460 (MH⁺).C₁₉H₁₉BrFN₇O requires 459 131 D66 CH₂

Found 426 (MH⁺).C₂₀H₂₀ ⁷⁹BrFN₅O requires 425 132 D66 CH₂

Found 474 (MH⁺).C₂₀H₂₁ ⁷⁹BrFN₇O requires 473 133 D66 CH₂

Found 506 (MH⁺).C₂₁H₂₁ ⁷⁹BrFN₅O₂S requires 505 134 D66 CH₂

Found 457 (MH⁺).C₂₀H₂₁ ⁷⁹BrN₆O₂ requires 456 135 D66 CH₂

Found 426 (MH⁺).C₂₀H₂₀ ⁷⁹BrN₅O requires 425 136 D68 CH₂

Found 447 (MH⁺).C₂₄H₂₀F₂N₆O requires 446 137 D68 CH₂

Found 458 (MH⁺).C₂₆H₂₁F₂N₅O requires 457 138 D68 CH₂

Found 522 (MH⁺).C₂₇H₂₂F₃N₅OS requires 521 139 D68 CH₂

Found 457 (MH⁺).C₂₇H₂₂F₂N₄O requires 456 140 D68 CH₂

Found 491 (MH⁺).C₂₆H₂₁F₃N₆O requires 490 141 D68 CH₂

Found 446 (MH⁺).C₂₅H₂₁F₂N₅O requires 445 142 D68 CH₂

Found 464 (MH⁺).C₂₄H₁₉F₂N₅OS requires 463 143 D29 CH₂

Found 433 (MH⁺).C₂₅H₂₂F₂N₄O requires 432 144 D29 CH₂

Found 441 (MH⁺).C₂₃H₁₉F₃N₄O₂ requires 440 145 D29 CH₂

Found 441 (MH⁺).C₂₃H₁₉F₃N₄O₂ requires 440 146 D29 CH₂

Found 441 (MH⁺).C₂₃H₁₉F₃N₄O₂ requires 440 147 D29 CH₂

Found 459 (MH⁺).C₂₃H₁₈F₄N₄O₂ requires 458 148 D62 CH₂

Found 405 (MH⁺).C₂₂H₂₁FN₆O requires 404 149 D62 CH₂

Found 419 (MH⁺).C₂₃H₂₃FN₆O requires 418 150 D64 CH₂

Found 419 (MH⁺).C₂₃H₂₃FN₆O requires 418 151 D66 CH₂

Found 558 (MH⁺).C₂₆H₃₂ ⁷⁹BrN₅O₂S requires 557 152 D29 CH₂

Found 566 (MH⁺).C₃₀H₃₃F₂N₅O₂S requires 565 153 D29 CH₂

Found 427 (MH⁺).C₂₀H₂₀BrN₅O requires 426 154 D29 CH₂

Found 436 (MH⁺).C₂₄H₂₃F₂N₅O requires 435 155 D29 CH₂

Found 422 (MH⁺).C₂₃H₂₁F₂N₅O requires 421 156 D29 CH₂

Found 441 (MH⁺).C₂₁H₁₈F₂N₆OS requires 440 157 D29 CH₂

Found 441 (MH⁺).C₂₃H₂₂F₂N₄O₃ requires 440 158 D29 CH₂

Found 538 (MH⁺).C₂₈H₃₀F₃N₇O requires 537 159 D66 CH₂

Found 530 (MH⁺).C₂₄H₂₉ ⁷⁹BrFN₇O requires 529 160 D49 CH₂

Found 490 (MH⁺).C₂₆H₂₈FN₇O₂ requires 489 161 D49 CH₂

Found 388 (MH⁺).C₂₁H₂₁N₇O requires 387 162 D66 CH₂

Found 415 (MH⁺)C₁₈H₁₉ ⁷⁹BrN₆O requires 414 163 D66 CH₂

Found 415 (MH⁺).C₁₉H₁₉ ⁷⁹BrN₄O₂ requires 414 164 D66 CH₂

Found (MH⁺) 405C₁₈H₂₁ ⁷⁹BrN₄O₂ requires 404 165 D66 CH₂

Found 426 (MH⁺)C₂₀H₂₀ ⁷⁹BrN₅O requires 425 166 D29 CH₂

Found 484 (MH⁺).C₂₆H₃₁F₂N₅O₂ requires 483 170 D66 CH₂

Found 473 (MH⁺).C₂₁H₂₂ ⁷⁹BrFN₆O requires 472 175 D66 CH₂

Found 375 (MH⁺)C₁₇H₁₉ ⁷⁹BrN₄O requires 374. 199 D7 O

Found 420 (MH⁺)C₂₂H₂₁N₅O₄ requires 419. 204 D82 CH₂

Found 454 (MH⁺).C₂₄H₂₂F₃N₅O requires 453 205 D82 CH₂

Found 440 (MH⁺).C₂₃H₂₀F₃N₅O requires 439. 206 D82 CH₂

Found 438 (MH⁺).C₂₃H₂₁F₂N₅O₂ requires 437. 207 D82 CH₂

Found 396 (MH⁺).C₂₂H₁₉F₂N₃O₂ requires 395. 230 D66 CH₂

Found 446 (MH⁺).C₁₉H₂₀ ⁷⁹BrN₅O₃ requires 445. 231 D66 CH₂

Found 570 (MH⁺).C₂₇H₃₃ ⁷⁹BrFN₇O requires 569. 241 D66 CH₂

Found 454 (MH⁺).C₂₂H₂₄ ⁷⁹BrN₅O requires 453 242 D66 CH₂

Found 448 (MNa⁺).C₂₀H₂₀ ⁷⁹BrN₅O requires 425. 243 D66 CH₂

Found 440 (MH⁺).C₂₁H₂₂ ⁷⁹BrN₅O requires 439. 244 D66 CH₂

Found 440 (MH⁺).C₂₁H₂₂ ⁷⁹BrN₅O requires 439. 245 D66 CH₂

Found 443 (MH⁺).C₁₇H₁₇ ⁷⁹Br³⁵Cl₂N₄O requires 442. 246 D66 CH₂

Found 474 (MH⁺).C₂₁H₂₁ ⁷⁹Br³⁵ClN₅O requires 473. 259 D80 O

Found 476 (MH⁺).C₂₁H₁₉ ⁷⁹BrFN₃O₂Srequires 475. 260 D66 CH₂

Found 454 (MH⁺).C₂₂H₂₄ ⁷⁹BrN₅O requires 453. 261 D66 CH₂

Found 502 (MH⁺).C₂₆H₂₄ ⁷⁹BrN₅O requires 501. 262 D66 CH₂

Found 440 (MH⁺).C₂₁H₂₂ ⁷⁹BrN₅O requires 439. 263 D66 CH₂

Found 504 (MH⁺).C₂₀H₁₉ ⁷⁹Br₂N₅O requires 503. 264 D66 CH₂

Found 440 (MH⁺).C₂₁H₂₂ ⁷⁹BrN₅O requires 439. 265 D66 CH₂

Found 504 (MH⁺).C₂₀H₁₉ ⁷⁹Br₂N₅O requires 503. 266 D66 CH₂

Found 544 (MH⁺).C₂₅H₃₁ ⁷⁹BrFN₇O requires 543.

EXAMPLE 931-{2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4-fluoro-phenyl)-2-H-pyrazol-3-yl]-methanone

The amine of D31 (0.085 g) in dimethylformamide (3 ml) was treated with4-(4-fluoro-phenyl)-2H-pyrazole-3-carboxylic acid (0.125 g),diisopropylethylamine (0.07 ml) and[0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate] (0.11 g). the mixture was shaken for 48 hours.Solvent was removed at reduced pressure and the residue extracted withdichloromethane. The filtrate was evaporated under reduced pressure andthe residue column chromatographed (silica gel, 3% methanol/diethylether) to give the title compound (0.1 g).

Mass Spectrum (API⁺): Found 453 (MH⁺). C₂₃H₁₉F₃N₆O requires 452.

Mass Spectrum (Electrospray Example Amine Ar² Ar¹ LC/MS), API⁺ 94 D31

Found 484 (MH⁺).C₂₄H₂₀F₃N₅OSrequires 483 95 D31

Found 467 (MH⁺).C₂₄H₂₁F₃N₆Orequires 466 96 D31

Found 468 (MH⁺).C₂₃H₂₀F₃N₇Orequires 467 97 D31

Found 394 (MH⁺).C₂₁H₁₇F₂N₅Orequires 393 98 D31

Found 419 (MH⁺).C₂₄H₂₀F₂N₄Orequires 418 99 D31

Found 478 (MH⁺).C₂₁H₁₉BrF₂N₄O₂requires 477 100 D31

Found 451 (MH⁺).C₂₃H₂₀F₂N₆O₂requires 450 101 D45

Found 484 (MH⁺).C₂₄H₂₀F₃N₅OSrequires 483 102 D45

Found 470 (MH⁺).C₂₃H₁₈F₃N₅OSrequires 469 103 D45

Found 451 (MH⁺).C₂₃H₂₀F₂N₆O₂requires 450 104 D45

Found 453 (MH⁺).C₂₃H₁₉F₃N₆Orequires 452 119 D45

Found 481 (MH⁺).C₂₅H₂₃F₃N₆Orequires 480 120 D45

Found 454 (MH⁺).C₂₂H₁₈F₃N₇Orequires 453 167 D70

Found 459 (MH⁺).C₂₀H₂₀ ⁷⁹BrFN₆Orequires 458 168 D45

Found 470 (MH⁺).C₂₃H₁₈F₃N₅OSrequires 469 169 D45

Found 467 (MH⁺).C₂₄H₂₁F₃N₆Orequires 466 176 D70

Found 514 (MNa⁺)C₂₀H₁₉ ⁷⁹BrFN₅O₂Srequires 491. 177 D70

Found 445 (MH⁺).C₁₉H₁₈ ⁷⁹BrFN₆Orequires 444. 178 D70

Found 434 (MNa⁺).C₁₉H₁₈ ⁷⁹BrN₅Orequires 411. 179 D70

Found 405 (MH⁺).C₁₈H₂₁ ⁷⁹BrN₄O₂requires 404. 180 D70

Found 458 (MH⁺).C₂₀H₂₀ ⁷⁹BrN₅OSrequires 457. 181 D70

Found 559 (MH⁺).C₂₅H₃₁ ⁷⁹BrN₆O₂Srequires 558. 182 D70

Found 419 (MH⁺).C₁₉H₂₃ ⁷⁹BrN₄O₂requires 418. 183 D70

Found 419 (MH⁺).C₁₉H₂₃ ⁷⁹BrN₄O₂requires 418. 184 D70

Found 467 (MH⁺).C₂₃H₂₃ ⁷⁹BrN₄O₂requires 466. 185 D70

Found 447 (MH⁺).C₂₀H₂₃ ⁷⁹BrN₄O₃requires 446. 186 D70

Found 435 (MH⁺).C₁₉H₂₃ ⁷⁹BrN₄O₃requires 434. 187 D70

Found 419 (MH⁺).C₁₉H₂₃ ⁷⁹BrN₄O₂requires 418 188 D70

Found 455 (MH⁺).C₂₂H₂₃ ⁷⁹BrN₄O₂requires 454. 189 D70

Found 476 (MH⁺).C₂₀H₁₉ ⁷⁹BrFN₅OSrequires 475. 190 D70

Found 476 (MH⁺).C₂₀H₁₉ ⁷⁹BrFN₅OSrequires 475. 191 D70

Found 462 (MH⁺).C₁₉H₁₇ ⁷⁹BrFN₅OSrequires 461. 192 D70

Found 444 (MH⁺).C₁₉H₁₈ ⁷⁹BrN₅OSrequires 443. 193 D70

Found 458 (MH⁺).C₂₀H₂₀ ⁷⁹BrN₅OSrequires 457. 201 D70

Found 462 (MH⁺).C₂₀H₁₇ ⁷⁹BrFN₅OSrequires 461. 202 D70

Found 488 (MH⁺).C₂₁H₂₂BrN₅O₂Srequires 487. 209 D70

Found 505 (MH⁺)C₂₁H₂₂ ⁷⁹BrFN₆OSrequires 504 210 D70

Found 459 (MH⁺).C₁₉H₁₉ ⁷⁹BrN₆OSrequires 458. 211 D70

Found 488 (MH⁺).C₂₁H₂₂ ⁷⁹BrN₅O₂Srequires 487. 212 D70

Found 461 (MH⁺)C₂₀H₁₈ ⁷⁹BrFN₄OSrequires 460. 213 D70

Found 460 (MNa⁺).C₂₁H₂₀ ⁷⁹BrN₅Orequires 437. 214 D70

Found 461 (MH⁺).C₁₉H₁₈ ⁷⁹BrFN₆O₂requires 460. 215 D70

Found 473 (MH⁺).C₂₁H₂₁ ⁷⁹BrN₄O₂requires 472. 219 D70

Found 492 (MH⁺).C₂₀H₁₉ ⁷⁹BrFN₅O₂Srequires 491. 220 D70

Found 461 (MH⁺).C₁₉H₁₈ ⁷⁹BrFN₆O₂requires 460. 221 D70

Found 443 (MH⁺).C₂₀H₁₉ ⁷⁹BrN₄OSrequires 442. 222 D70

Found 462 (MH⁺).C₂₃H₂₀ ⁷⁹BrN₅Orequires 461. 223 D70

Found 473 (MH⁺).C₂₁H₂₁ ⁷⁹BrN₄O₂Srequires 472. 224 D70

Found 449 (MNa⁺).C₁₉H₁₉ ⁷⁹BrN₆Orequires 426. 232 D70

Found 516 (MH⁺).C₂₃H₂₇ ⁷⁹BrFN₇Orequires 515. 233 D70

Found 490 (MH⁺).C₂₁H₂₁ ⁷⁹BrFN₅OSrequires 489. 247 D95

Found 448 (MH⁺).C₂₀H₁₉ ³⁵Cl₂N₅OSrequires 447. 248 D93

Found 407 (MH⁺).C₂₁H₂₂N₆O₃requires 406. 250 D70

Found 440 (MH⁺).C₂₁H₂₂ ⁷⁹BrN₅Orequires 439. 251 D95

Found 461 (MH⁺).C₂₁H₂₂ ³⁵ClFN₆OSrequires 460. 252 D95

Found 416 (MNa⁺).C₂₁H₂₀ ³⁵ClN₅Orequires 393. 253 D95

Found 468 (MNa⁺).C₂₁H₂₁ ³⁵ClFN₅OSrequires 445. 254 D95

Found 393 (MH⁺).C₂₂H₂₁ ³⁵ClN₄Orequires 392. 255 D70

Found 429 (MH⁺).C₁₆H₁₅ ⁷⁹Br₃₅Cl₂N₄Orequires 428. 256 D95

Found 520 (MH⁺).C₂₄H₂₇ ³⁵Cl₂N₅O₂Srequires 519. 257 D95

Found 427 (MH⁺).C₂₁H₂₃ ³⁵ClN₆O₂requires 426. 258 D70

Found 471 (MH⁺).C₂₁H₂₃ ⁷⁹BrN₆O₂requires 470.

EXAMPLE 1051-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-[(S)-2-(oxazolo[4,5-b]]pyridin-2-ylaminomethyl)-piperidin-1-yl]-methanone

The compound of D41 (0.51 g) and 2-methylsulfanyl-oxazolo[4,5-b]pyridine(0.25 g) were combined and heated under argon at 90° C. for 18 hours Themixture was column chromatographed (5% methanol, diethyl ether eluant)to give the title compound (0.26 g) Mass Spectrum (API⁺): Found 419(MH⁺). C₂₂H₂₂N₆O₃ requires 418.

EXAMPLE 1061-[2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1-{(R)-2-[(methyl-oxazolo[4,5-b]pyridin-2-yl-amino)-methyl]piperidin-1-yl}-methanone

The title compound (0.015 g) was prepared from the compound of D43 (0.15g) according to the method of Example 105.

Mass Spectrum (API⁺): Found 433 (MH⁺). C₂₃H₂₄N₆O₃ requires 432.

EXAMPLE 1076-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-methyl-amino]-nicotinonitrile

The title compound (0.078 g) was prepared from the compound of D60 (0.45g) and 2-chloro-5-cyanopyridine (0.189 g) according to the method of D26

Mass Spectrum (API⁺): Found 433 (MH⁺). C₂₄H₂₅FN₆O requires 432.

EXAMPLE 1081-((S)-2-{[(6,7-Difluoro-quinoxalin-2-yl)-methyl-amino]-methyl}-piperidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

The title compound (0.031 g) was prepared from the compound of D60 (0.15g) and 2-chloro-6,7-difluoroquinoxaline (0.091 g) according to themethod of D26

Mass Spectrum (API⁺): Found 495 (MH⁺). C₂₆H₂₅F₃N₆O requires 494.

EXAMPLE 1711-{2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone

A mixture of1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone(0.5 g) and 1-ethoxyvinyl)tributyltin (0.42 ml)tetrakis(triphenylphosphine)palladium[0} (0.06 g) was boiled in dioxane(8 ml) for 16 h. 2N Hydrochloric acid was added, the mixture stirred for90 min, water was added and the mixture extracted (×3) with ethylacetate. The combined ethyl acetate extracts were dried, solvent removedat reduced pressure and the residue column chromatographed (silica gel,ethyl acetate→2% methanol ethyl acetate to give the title compound (0.3g) as a yellow foam.

Mass Spectrum (API⁺): Found 437 (MH⁺). C₂₃H₂₅FN₆O₂ requires 436.

EXAMPLE 1721-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-1-((S)-2-{[5-(1-hydroxy-ethyl)-pyrimidin-2-ylamino]-methyl}-piperidin-1-yl)-methanone

1-{2-[((S)-1-{1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone(0.2 g) was dissolved in methanol 20 ml) and sodium borohydride (0.4 g)added. The reaction was stirred overnight, water was added and stirringcontinued for 30 min. The reaction mixture was extracted with ethylacetate (×3), the organic extracts combined, dried (MgSO₄) and solventremoved at reduced pressure to give the title compound as a colourlessfoam.

Mass Spectrum (API⁺): Found 439 (MH⁺). C₂₃H₂₇FN₆O₂ requires 438.

EXAMPLE 1732-[((S)-1-{(1-[4-(4-Fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile

1-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone(0.35 g) in N-methylpyrrolidinone (10 ml) containing copper(I) cyanide(0.13 g) was heated to reflux for 5 h. The reaction mixture was dilutedwith water, filtered (Kieselguhr) and the filtrate extracted with ethylacetate. The ethyl acetate phase was washed with water and brine, dried(MgSO4), filtered and solvent removed at reduced pressure. The residuewas column chromatographed (silica gel; ethyl acetate:pentane 1:1→ethylacetate eluant), the appropriate fractions combined and solvent removedat reduced pressure to give the title compound (0.019 g).

Mass Spectrum (API⁺): Found 420 (MH⁺). C₂₂H₂₂FN₇O requires 419.

EXAMPLE 1743-(1-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanoyl)-N-methyl-benzamide

The compound of description 71 (0.10 g) was dissolved indimethylformamide (5 ml) containing HATU (0.095 g) anddiisopropylethylamine (0.131 ul) and stirred for 30 in. Methylamine (1Min tetrahydrofuran, 0.125 ml) was added and stirring continued for 16.The reaction mixture was diluted with diethyl ether, washed with water(×3), saturated brine and dried (MgSO4). Solvent was removed at reducedpressure and the residue column chromatographed (silica gel; ethylacetate→10% methanol:ethyl acetate to give the title compound (0.018 g).

Mass Spectrum (API⁺): Found 440 (MH⁺). C₂₃H₂₃F₂N₅O₂ requires 439.

EXAMPLE 1941-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

A mixture of the amine of D70 (0.070 g),5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.065 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (0.042g) and 1-hydroxybenzotriazole hydrate (0.037 g) in dimethylformamide (2ml) was stirred at ambient temperature for 18 h, evaporated in vacuo andthe residue partitioned between ethyl acetate and water. The organiclayer was dried (Na₂SO₄), evaporated and the residue chromatographed onsilica gel eluting with a 30%-100% ethyl acetate in pentane gradient toafford the title product (0.083 g) as a white solid. Mass Spectrum(Electrospray LC/MS), API⁺: Found 476 (MH⁺). C₂₀H₁₉ ⁷⁹BrFN₅OS requires475.

EXAMPLE 1951-{(S)-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone

The title compound (0.053 g) was obtained from the amine of D70 (0.070g) and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoic acid (0.056 g) usingthe method of Example 194. Mass Spectrum (Electrospray LC/MS): Found 443(MH⁺). C₁₉H₁₉ ⁷⁹BrN₆O₂ requires 442.

EXAMPLE 1961-{(S)-2-[5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (0.078 g) was obtained from the amine of D70 (0.077g) and 5-(4-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.076 g)according to the method of Example 32. Mass spectrum (ElectrosprayLC/MS), API⁺: Found 492 (MH⁺). C₂₀H₁₉ ⁷⁹Br³⁵ClN₅OS requires 491.

EXAMPLE 1971-{(S)-2-[(5-Bromo-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (0.135 g) was obtained from the amine of D74 (0.11 g)and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.12 g)according to the method of Example 32. Mass Spectrum API⁺: Found 475(MH⁺). C₂₁H₂₀ ⁷⁹BrFN₄OS requires 474.

EXAMPLE 1981-{(S)-2-[(5-Bromo-pyridin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

The title compound (0.10 g) was obtained from the amine of D74 (0.11 g)and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (0.12 g)according to the method of Example 32. Mass Spectrum API⁺: Found 458(MH⁺). C₂₁H₂₁ ⁷⁹BrFN₅O requires 457.

EXAMPLE 2001-{3-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-morpholin-4-yl}-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

The title compound (0.393 g) was obtained from the compound of D80 (0.3g) and 4-(4-fluorophenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (0.242g) according to the method of Example 32. Mass Spectrum (API⁺): Found475 (MH⁺). C₂₀H₂₀ ⁷⁹BrFN₆O₂ requires 474.

EXAMPLE 2033,5-Difluoro-4-[((S)-1-{1-[5-(4-fluorophenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-ylmethyl)-amino]-benzonitrile

The title compound (0.090 g) was obtained from the compound of D82(0.073 g) and 5-(4-fluorophenyl)-2-methyl-thiazole-4-carboxylic acid(0.069 g) according to the method of Example 32. Mass Spectrum(Electrospray LC/MS): Found 471. C₂₄H₂₁F₃N₄OS requires 470.

EXAMPLE 2083,5-Difluoro-4-[((S)-1-{1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-pyrrolidin-2-ylmethyl)-amino]-benzonitrile

The title compound (0.09 g) was obtained from the compound of D84 and5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.095 g)according to the method of Example 32. Mass Spectrum (ElectrosprayLC/MS): Found 457 (MH⁺). C₂₃H₁₉F₃N₄OS requires 456.

EXAMPLE 2161-{(S)-2-[(5-Ethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (0.05 g) was obtained from the compound of D86 (0.07g) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.068 g)according to the method of Example 32. Mass Spectrum (ElectrosprayLC/AS): Found 426 (MH⁺). C₂₂H₂₄FN₅OS requires 425.

EXAMPLE 2171-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (0.1 g) was obtained from the compound of D91 (0.275g) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.285 g)according to the method of Example 32. Mass Spectrum (ElectrosprayLC/MS): Found 490 (MH⁺). C₂₁H₂₁ ⁷⁹BrFN₅OS requires 489.

EXAMPLE 2181-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrrolidin-1-yl)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

The title compound (0.02 g) was obtained from the compound of D91 (0.275g) and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (0.260g) according to the method of Example 32. Mass Spectrum (ElectrosprayLC/MS): Found 473 (MH⁺). C₂₁H₂₂ ⁷⁹BrFN₆O requires 472.

EXAMPLE 2251-{2-[((S)-1-{1-[5-(4-Chloro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-pyrrolidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone

The title product (0.04 g) was obtained from the compound of D93 (0.133g) and 5-(4-chloro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.076 g)using a similar procedure to that described in Example 32. Mass Spectrum(Electrospray LC/MS): Found 456 (MH⁺). C₂₂H₂₂ ³⁵ClN₅O₂S requires 455.

EXAMPLE 2261-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title product (0.095 g) was obtained from the amine of D95 (0.064 g)and 5-(4-fluorophenyl)-2-methyl-thiazole-4-carboxylic acid (0.071 g)using the method of Example 32. Mass Spectrum (Electrospray LC/MS):Found 432 (MH⁺). C₂₀H₁₉ ³⁵ClFN₅OS requires 431.

EXAMPLE 2271-{(S)-2-[(5-Chloro-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone

The title compound (0.052 g) was obtained from the amine of D95 (0.064g) and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoic acid (0.061 g)according to the method of Example 32. Mass Spectrum (ElectrosprayLC/MS): Found 399 (MH⁺). C₁₉H₁₉ ³⁵ClN₆O₂ requires 398.

EXAMPLE 2281-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(5-methyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone

To the compound of Example 194 (0.36 g) in dimethylformamide was addedlithium chloride (0.096 g), tetramethyl tin (0.126 ml) anddichlorobis(triphenylphosphine) palladium (0) (0.035 g) and theresulting mixture heated at 100° C. under argon for 18 h. The reactionwas then evaporated, diluted with dichloromethane, filtered and thefiltrate washed with water, dried and evaporated. Chromatography of theresidue on silica gel, eluting with methanol-dichloromethane mixtures,afforded the title product (0.2 g) as a yellow amorphous solid. MassSpectrum (API⁺): Found 412 (MH⁺). C₂₁H₂₂FN₅OS requires 411.

EXAMPLE 2296-[((S)-1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-pyrrolidin-2-ylmethyl)-amino]-nicotinonitrile

A mixture of the amine of D97 (0.134 g),5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (0.172 g), EDC(0.139 g) and 1-hydroxybenzotriazole (0.01 g) in dichloromethane (8 ml)was stirred at ambient temperature for 7 days. The reaction was washedwith saturated aqueous sodium bicarbonate solution, dried andevaporated. Chromatography of the residue on silica gel, eluting withethyl acetate—hexane mixtures afforded the title product (0.196 g). MassSpectrum (Electrospray LC/MS): Found 422 (MH⁺). C₂₂H₂₀FN₅OS requires421.

EXAMPLE 2341-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(6-methyl-2-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone

The title product (0.095 g) was obtained from the amine of D101 (0.15 g)and the compound of D98 (0.14 g) using a similar method to thatdescribed in D69. Mass Spectrum (Electrospray LC/MS): Found 458 (MH⁺).C₂₂H₂₄FN₅OS₂ requires 457.

EXAMPLE 2351-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(2-methylsulfanyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-1-yl}-methanone

The title compound (0.05 g) was obtained from the amine of D101 (0.15 g)and 4-chloro-2-methylsulfanyl-pyrimidine (0.076 g) using a similarmethod to that described in D69. Mass Spectrum (Electrospray LC/MS):Found 444 (MH⁺). C₂₁H₂₂FN₅OS₂ requires 443.

The following compounds were prepared using methods similar to thatdescribed in Examples 234 and 235.

Mass Spectrum (Electrospray Example Amine Y Ar² Ar¹ LC/MS), API⁺ 236D101 Bond

Found 494 (MH⁺).C₂₃H₂₃F₄N₅OSrequires 493. 237 D101 Bond

Found 426 (MH⁺).C₂₂H₂₄FN₅OSrequires 425. 238 D101 Bond

Found 466 (MH⁺).C₂₁H₁₉F₄N₅OSrequires 465.

EXAMPLE 2391-(3-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-morpholin-4-yl)-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (0.056 g) was obtained from the compound of D105(0.095 g) and 5-(4-fluorophenyl)-2-methyl-thiazole-4-carboxylic acid(0.10 g) according to the method of Example 32. Mass Spectrum(Electrospray LC/MS): Found 506 (MH⁺). C₂₁H₂₁ ⁷⁹BrFN₅O₂S requires 505.

EXAMPLE 2401-(3-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-morpholin-4-yl)-1-[2-(4-fluoro-phenyl)-thiophen-3-yl]-methanone

To the compound of D105 (0.095 g) in dichloromethane (8 ml) containingtriethylamine (0.06 ml) was added2-(4-fluorophenyl)-thiophene-3-carbonyl chloride (0.084 g). After 72 hat ambient temperature the reaction mixture was washed with brine, driedand evaporated; the residue was chromatographed on silica gel, elutingwith ethyl acetate-pentane mixtures to afford the title product (0.093g). Mass Spectrum (Electrospray LC/MS): Found 491 (MH⁺). C₂₁H₂₀⁷⁹BrFN₄O₂S requires 490.

EXAMPLE 2491-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{(S)-2-[(5-trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone

To the compound from Example 194 (0.36 g) in dimethylformamide (5 ml)was added potassium trifluoroacetate (0.23 g), copper iodide (0.3 g) andtoluene (5 ml) and the resulting mixture heated at reflux underDean-Stark conditions for 3 h, before refluxing for a further 20 h. Thereaction mixture was cooled, poured into water/ether and filteredthrough kieselguhr. The aqueous layer from the filtrate was extractedwith ether, and the combined ether extracts washed with water, dried andevaporated. The aqueous was re-extracted with dichloromethane and theextract evaporated. The combined extracts were chromatographed on silicagel, eluting with methanol-dichloromethane mixtures, to afford the titleproduct (0.001 g). Mass Spectrum (Electrospray LC/MS): Found 466 (MH⁺).C₂₁H₁₉F₄N₅OS requires 465.

The compounds in the table below were prepared using methods describedabove

Mass Spectrum (Electrospray Example X R Ar² Ar¹ LC/MS), API⁺ 267 CH₂ H

Found 486 (MH⁺).C₂₄H₂₉ ³⁵ClFN₇Orequires 485. 268 CH₂ H

Found 526 (MH⁺).C₂₇H₃₃ ³⁵ClFN₇Orequires 525. 269 CH₂ H

Found 540 (MH⁺).C₂₈H₃₅ ³⁵ClFN₇Orequires 539. 270 CH₂ Me

Found 440 (MH⁺).C₂₁H₂₂ ⁷⁹BrN₅Orequires 439. 271 CH₂ Me

Found 457 (MH⁺).C₁₈H₁₉ ⁷⁹Br³⁵Cl₂N₄Orequires 456. 272 CH₂ Me

Found 489 (MH⁺).C₂₃H₂₆ ³⁵ClFN₆OSrequireS 488. 273 CH₂ Me

Found 454 (MH⁺).C₂₂H₂₄ ⁷⁹BrN₅Orequires 453. 274 CH₂ Me

Found: 454 (MH⁺).C₂₂H₂₄ ⁷⁹BrN₅Orequires 453. 275 CH₂ H

Found 446 (MH⁺).C₂₁H₂₁ ³⁵ClFN₅OSrequires 445.

It is understood that the present invention covers all combinations ofparticular and preferred groups described herein above.

Determination of Orexin-1 Receptor Antagonist Activity

The orexin-1 receptor antagonist activity of the compounds of formula(I) was determined in accordance with the following experimental method.

Experimental Method

CHO-DG44 cells expressing the human orexin-1 receptor were grown in cellmedium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4mg/mL G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calfserum from Gibco BRL. The cells were seeded at 20,000 cells/100 μl/wellinto 96-well black clear bottom sterile plates from Costar which hadbeen pre-coated with 10 μg/well of poly-L-lysine from SIGMA. The seededplates were incubated overnight at 37 C in 5% CO₂.

Agonists were prepared as 1 mM stocks in water:DMSO (1:1). EC50 values(the concentration required to produce 50% maximal response) wereestimated using 11× half log unit dilutions (Biomek 2000, Beckman) inTyrode's buffer containing probenecid (10 mM HEPES with 145 mM NaCl, 10mM glucose, 2.5 mM KCl, 1.5 mM CaCl₂, 1.2 mM MgCl₂ and 2.5 mMprobenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO(100%). Antagonist IC50 values (the concentration of compound needed toinhibit 50% of the agonist response) were determined against 3.0 nMhuman orexin-A using 11× half log unit dilutions in Tyrode's buffercontaining 10% DMSO and probenecid.

On the day of assay 50 μl of cell medium containing probenecid (Sigma)and Fluo3AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec)to each well to give final concentrations of 2.5 mM and 4 μM,respectively. The 96-well plates were incubated for 60 min at 37 C in 5%CO2. The loading solution containing dye was then aspirated and cellswere washed with 4×150 μl Tyrode's buffer containing probenecid and 0.1%gelatin (Denley Cell Wash). The volume of buffer left in each well was125 μl. Antagonist or buffer (25 μl) was added (Quadra) the cell platesgently shaken and incubated at 37 C in 5% CO₂ for 30 minutes. Cellplates were then transferred to the Fluorescent Imaging Plate Reader(FLIPR, Molecular Devices) instrument. Prior to drug addition a singleimage of the cell plate was taken (signal test), to evaluate dye loadingconsistency. The run protocol used 60 images taken at 1 second intervalsfollowed by a further 24 images at 5 second intervals. Agonists wereadded (by the FLIPR) after 20 seconds (during continuous reading). Fromeach well, peak fluorescence was determined over the whole assay periodand the mean of readings 1-19 inclusive was subtracted from this figure.The peak increase in fluorescence was plotted against compoundconcentration and iteratively curve fitted using a four parameterlogistic fit (as described by Bowen and Jerman, TiPS, 1995, 16, 413-417)to generate a concentration effect value. Antagonist Kb values werecalculated using the equation:

Kb=IC50/(1+([3/EC50])

where EC50 was the potency of human orexin-A determined in the assay (innM terms) and IC50 is expressed in molar terms.

Compounds of Examples tested according to this method had pKb values inthe range 6.7-9.7 at the human cloned orexin-1 receptor.

The orexin-2 receptor antagonist activity of the compounds of formula(I) was determined in accordance with the following experimental method.

Experimental Method

CHO-DG44 cells expressing the human orexin-2 receptor were grown in cellmedium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4mg/mL G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calfserum from Gibco BRL. The cells were seeded at 20,000 cells/100 μl/wellinto 96-well black clear bottom sterile plates from Costar which hadbeen pre-coated with 10 μg/well of poly-L-lysine from SIGMA. The seededplates were incubated overnight at 37 C in 5% CO₂.

Agonists were prepared as 1 mM stocks in water:DMSO (1:1). EC50 values(the concentration required to produce 50% maximal response) wereestimated using 11× half log unit dilutions (Biomek 2000, Beckman) inTyrode's buffer containing probenecid (10 mM HEPES with 145 mM NaCl, 10mM glucose, 2.5 mM KCl, 1.5 mM CaCl₂, 1.2 mM MgCl₂ and 2.5 mMprobenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO(100%). Antagonist IC50 values (the concentration of compound needed toinhibit 50% of the agonist response) were determined against 10.0 nMhuman orexin-A using 11× half log unit dilutions in Tyrode's buffercontaining 10% DMSO and probenecid.

On the day of assay 50 μl of cell medium containing probenecid (Sigma)and Fluo3AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec)to each well to give final concentrations of 2.5 mM and 4 μM,respectively. The 96-well plates were incubated for 60 min at 37 C in 5%CO₂. The loading solution containing dye was then aspirated and cellswere washed with 4×150 μl Tyrode's buffer containing probenecid and 0.1%gelatin (Denley Cell Wash). The volume of buffer left in each well was125 μl. Antagonist or buffer (25 μl) was added (Quadra) the cell platesgently shaken and incubated at 37 C in 5% CO₂ for 30 min. Cell plateswere then transferred to the Fluorescent Imaging Plate Reader (FLIPR,Molecular Devices) instrument. Prior to drug addition a single image ofthe cell plate was taken (signal test), to evaluate dye loadingconsistency. The run protocol used 60 images taken at 1 second intervalsfollowed by a further 24 images at 5 second intervals. Agonists wereadded (by the FLIPR) after 20 sec (during continuous reading). From eachwell, peak fluorescence was determined over the whole assay period andthe mean of readings 1-19 inclusive was subtracted from this figure. Thepeak increase in fluorescence was plotted against compound concentrationand iteratively curve fitted using a four parameter logistic fit (asdescribed by Bowen and Jerman, TiPS, 1995, 16, 413-417) to generate aconcentration effect value. Antagonist Kb values were calculated usingthe equation:

Kb=IC50/(1+([3/EC50])

where EC50 was the potency of human orexin-A determined in the assay (innM terms) and IC50 is expressed in molar terms.

Compounds of Examples tested according to this method had pKb values inthe range <6.3-9.1 at the human cloned orexin-2 receptor.

The application of which this description and claims forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process, or use claims and may include, by way ofexample and without limitation the following claims:

1. A compound of formula (Ia):

wherein: Y represents a bond or a group (CH₂)_(n), wherein n represents1; Ar¹ is benzoxazolyl, benzothiazolyl, or benzimidazolyl; Ar²represents a phenyl group or a 5- or 6-membered heterocyclyl groupselected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl,pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl, andpyrazolyl, and wherein the phenyl or heterocyclyl group is substitutedby R¹ and is further optionally substituted, or Ar² represents anoptionally substituted naphthyl group or optionally substituted bicyclicheteroaromatic group selected from benzofuryl, benzimidazolyl,quinolinyl, quinoxalinyl, benzotriazolyl, benzothienyl, benzoxazolyl,naphthyridinyl, isoquinolyl, quinazolinyl, indolyl, benzothiazolyl, andbenzothiadiazolyl; R¹ represents hydrogen, optionally substituted(C₁₋₄)alkoxy, halo, cyano, optionally substituted (C₁₋₆)alkyl, or anoptionally substituted phenyl; wherein said optionally substituted Ar¹,Ar², and R¹ is optionally substituted by halogen, hydroxy, oxo, cyano,nitro, (C₁₋₄)alkyl, (C₁₋₄)alkoxy, hydroxy(C₁₋₄)alkyl,hydroxy(C₁₋₄)alkoxy, halo(C₁₋₄)alkyl, halo(C₁₋₄)alkoxy,aryl(C₁₋₄)alkoxy, (C₁₋₄)alkylthio, hydroxy(C₁₋₄)alkyl,(C₁₋₄)alkoxy(C₁₋₄)alkyl, (C₃₋₆)cycloalkyl(C₁₋₄)alkoxy, (C₁₋₄)alkanoyl,(C₁₋₄)alkoxycarbonyl, (C₁₋₄)alkylsulfonyl, (C₁₋₄)alkylsulfonyloxy,(C₁₋₄)alkylsulfonyl(C₁₋₄)alkyl, arylsulfonyl, arylsulfonyloxy,arylsulfonyl(C₁₋₄)alkyl, (C₁₋₄)alkylsulfonamido, (C₁₋₄)alkylamido,(C₁₋₄)alkylsulfonamido(C₁₋₄)alkyl, (C₁₋₄)alkylamido(C₁₋₄)alkyl,arylsulfonamido, arylcarboxamido, arylsulfonamido(C₁₋₄)alkyl,arylcarboxamido(C₁₋₄)alkyl, aroyl, aroyl(C₁₋₄)alkyl, aryl(C₁₋₄)alkanoyl,(C₁₋₄)acyl, aryl, aryl(C₁₋₄)alkyl, (C₁₋₄)alkylamino(C₁₄)alkyl,R^(a)R^(b)N—, R^(a)OCO(CH₂)_(r), R^(a)CON(R^(a))(CH₂)_(r),R^(a)R^(b)NCO(CH₂)_(r), R^(a)R^(b)NSO₂(CH₂)_(r) orR^(a)SO₂NR^(b)(CH₂)_(r), wherein r represents zero or an integer from 1to 4, or R^(a)R^(b)N(CH₂)n- or R^(a)R^(b)N(CH₂)nO-, wherein n representsan integer from 1 to 4, wherein each of R^(a) and R^(b) independentlyrepresents a hydrogen atom or a (C₁₋₄)alkyl group or R^(a)R^(b) formspart of a (C₃₋₆)azacycloalkane or (C₃₋₆)(2-oxo)azacycloalkane ring, orR^(a)R^(b)N(CH₂)n- or R^(a)R^(b)N(CH₂)_(n)O, where R^(a) with at leastone CH₂ of the (CH₂)n portion of the group form a (C₃₋₆)azacycloalkaneand R^(b) represents hydrogen, a (C₁₋₄)alkyl group or with the nitrogento which it is attached forms a second (C₃₋₆)azacycloalkane fused to thefirst (C₃₋₆)azacycloalkane; wherein when Y is a bond then Ar² can not be2-naphthyl; or a pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1, wherein Ar² represents an optionally substitutedphenyl, pyridyl, thiazolyl, pyrazolyl, benzofuryl, naphthyl, triazolyl,quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl,benzotriazolyl, benzothiazolyl, indolyl or thienyl.
 3. A compoundaccording to claim 1, wherein Ar² represents an optionally substitutedphenyl, pyridyl, thiazolyl, pyrazolyl, triazolyl, or thienyl.
 4. Acompound according to claim 1, wherein R¹ is selected from atrifluoromethoxy, methoxy, ethoxy, halo, cyano or an optionallysubstituted phenyl, pyridyl, pyrazolyl, pyrimidinyl, and oxadiazolylgroup.
 5. A pharmaceutical composition comprising a therapeuticallyeffective amount of the compound according to claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 6. A method of treating a disease or disorder wherean antagonist of a human orexin receptor is required, which comprisesadministering to a subject in need thereof an effective amount of thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein said disease or disorder is selected from obesity andobesity associated with Type II diabetes.
 7. A method of treatinginsomnia which comprises administering to a subject in need thereof aneffective amount of the compound according to claim 1, or apharmaceutically acceptable salt thereof.
 8. A compound selected from:1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-methyl-5-phenyl-thiazol-4-yl)-methanone;1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-biphenyl-2-yl-methanone;1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone;1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)-methanone;1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-naphthalen-1-yl-methanone;1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-methoxy-phenyl)-methanone;1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-iodo-phenyl)-methanone;1-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)-methanone;1-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone;1-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-biphenyl-2-yl-methanone;1-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-iodo-phenyl)-methanone1-[2-Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-phenyl-methanone;1-{2-[(1H-Benzoimidazol-2-ylamino)-methyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;1-{2-[(1H-Benzoimidazol-2-ylamino)-methyl]-piperidin-1-yl}-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone;1-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone;1-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy-phenyl)-methanone;1-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-biphenyl-2-yl-methanone;1-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-methyl-5-phenyl-thiazol-4-yl)-methanone;1-[(S)-2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone;1-[2-(Benzothiazol-2-ylaminomethyl)-piperidin-1-yl]-1-naphthalen-1-yl-methanone;1-(1H-Benzoimidazol-5-yl)-1-[(S)-2-(pyrido[2,3-b]pyrazin-2-ylaminomethyl)-piperidin-1-yl]-methanone;1-Benzo[b]thiophen-2-yl-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanone;1-(1H-Benzoimidazol-5-yl)-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanone;1-(1H-Benzotriazol-5-yl)-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanone;1-Benzothiazol-6-yl-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-1-yl}-methanone;2-{[(S)-1-(1-1H-Benzoimidazol-5-yl-methanoyl)-piperidin-2-ylmethyl]-amino}-6,7-difluoro-quinoline-3-carbonitrile;2-{[(S)-1-(1-Benzothiazol-6-yl-methanoyl)-piperidin-2-ylmethyl]-amino}-6,7-difluoro-quinoline-3-carbonitrile;1-(1H-Benzoimidazol-5-yl)-1-{(S)-2-[(5-bromo-pyrimidin-2-ylamino)-methyl]-piperidin-1-yl}-methanone;and a pharmaceutically acceptable salt thereof.